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Azhari HF, Dawson J. Clinical implications of fracture severity risk with pioglitazone: a systematic review and meta-analysis of clinical randomized trials. Front Pharmacol 2025; 16:1357309. [PMID: 40115256 PMCID: PMC11922898 DOI: 10.3389/fphar.2025.1357309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Accepted: 02/06/2025] [Indexed: 03/23/2025] Open
Abstract
Introduction Pioglitazone, a thiazolidinedione, effectively reduces stroke and cardiovascular events in individuals with type 2 diabetes, insulin resistance, and/or stroke. However, its potential to increase fracture risk, particularly among women and those with pre-existing skeletal conditions, has not yet been completely understood. This meta-analysis aims to clarify fracture risk associated with pioglitazone, thereby focusing on individuals with a history of stroke. Methods A systematic review was performed for clinical trials conducted up to March 2024, focusing on trials comparing pioglitazone to placebo or other antihyperglycemic drugs that reported fracture outcomes. Results From 860 trials identified, 78 satisfied the inclusion criteria: 34 with a high risk of bias, 8 with unclear risk, and 36 with low risk. The meta-analysis revealed an association between pioglitazone and a significant increase in fracture risk (risk ratio [RR] 1.21; 95% CI 1.01-1.45; P = 0.04), including non-serious (RR 1.25; 95% CI 1.03-1.51; P = 0.02) and serious fractures (RR 1.48; 95% CI 1.10-1.98; P = 0.01). Notably, the risk was exacerbated for low-energy fractures, particularly resulting from falls (RR 1.49; 95% CI 1.20-1.87; P = 0.0004), in insulin resistance individuals (RR 0.87; 95% CI 0.43-1.76; P = 0.69), and stroke survivors (RR 1.41; 95% CI 1.09-1.83; P = 0.008). Fractures were most frequently observed in lower extremities (RR 1.85; 95% CI 1.33-2.56; P = 0.0002), with women at a greater risk (RR 1.56; 95% CI 1.20-2.02; P = 0.0008). When compared with other antihyperglycemic drugs, no significant difference in fracture risk was noted (RR 1.08; 95% CI 0.73-1.59; P = 0.70), except rosiglitazone, which showed higher fracture risk (RR 1.42; 95% CI 1.23-1.64; P < 0.00001). Fracture risk was significant in the fixed-effect model but not in the random-effects model. Discussion Though pioglitazone offers several cardiovascular benefits, its association with increased fracture risk, especially among women and non-diabetic individuals post-stroke, warrants careful consideration. Individualized treatment interventions balancing cardiovascular and skeletal outcomes are essential, and further research is needed to optimize therapeutic strategies in this population. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42016038242, identifier CRD42016038242.
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Affiliation(s)
- Hala F Azhari
- College of Medicine and Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Jesse Dawson
- School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, United Kingdom
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Yao Q, Tsuboi K, Hongo H, Sakakibara M, Yamamoto T, Haraguchi-Kitakamae M, Ishizu H, Liu X, Shi Y, Li W, Cui J, Shimizu T, Amizuka N, Yokoyama A, Hasegawa T, Sakaguchi K. Histochemical assessment of the femora of spontaneously diabetic torii-lepr fa (SDT-fa/fa) rats that mimic type II diabetes. J Oral Biosci 2025; 67:100602. [PMID: 39706476 DOI: 10.1016/j.job.2024.100602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 12/17/2024] [Accepted: 12/18/2024] [Indexed: 12/23/2024]
Abstract
OBJECTIVE To elucidate the mechanisms underlying diabetic osteoporosis, we conducted a comprehensive histological examination of the femora of Spontaneously Diabetic Torii-Leprfa (SDT-fa/fa) rats, an established model of obesity-related type 2 diabetes. MATERIALS AND METHODS Femora from 12 30-week-old male SDT-fa/fa rats and age-matched Sprague-Dawley (SD) rats (controls) were used for detailed histochemical analyses, including tartrate-resistant acid phosphatase (TRAP), cathepsin K, tissue nonspecific alkaline phosphatase (ALP), phosphoethanolamine/phosphocholine phosphatase 1 (PHOSPHO1), dentin matrix protein 1 (DMP-1), matrix extracellular phosphoglycoprotein (MEPE), sclerostin, osteocalcin staining, silver impregnation, von Kossa staining, and micro-computed tomography (CT). RESULTS Micro-CT and hematoxylin-eosin staining demonstrated significantly reduced trabecular bone volume in the femoral metaphyses of SDT-fa/fa rats. Although the number of TRAP-positive osteoclasts per bone surface remained comparable between both groups, SDT-fa/fa rats exhibited reduced areas of ALP-positive and PHOSPHO1-reactive mature osteoblasts/BS. Silver impregnation revealed a well-organized osteocytic lacunar-canalicular system in both groups. However, immunostaining identified aberrant DMP-1 and MEPE expression localized predominantly in the lacunae in SDT-fa/fa rats and in the lacunae and canaliculi of SD rats. Additionally, intense osteocalcin and sclerostin immunoreactivity was detected in osteocytes, along with a higher proportion of osteocalcin-positive osteocytes in SDT-fa/fa rats, distinguishing them from controls. CONCLUSION SDT-fa/fa rats displayed a significant decline in osteoblastic function and distinctive distribution patterns of osteocyte-derived peptides, suggesting that this diabetic model may manifest alterations in osteoblastic activity and the osteocytic lacunar-canalicular network.
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Affiliation(s)
- Qi Yao
- Ultrastructure of Hard Tissues, Faculty of Dental Medicine, Hokkaido University, Sapporo, Japan; Oral Functional Prosthodontics, Faculty of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Kanako Tsuboi
- Department of Oral and Maxillofacial Surgery, Haibara General Hospital, Makinohara, Japan
| | - Hiromi Hongo
- Ultrastructure of Hard Tissues, Faculty of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Mako Sakakibara
- Ultrastructure of Hard Tissues, Faculty of Dental Medicine, Hokkaido University, Sapporo, Japan; Orthodontics, Faculty of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Tomomaya Yamamoto
- Ultrastructure of Hard Tissues, Faculty of Dental Medicine, Hokkaido University, Sapporo, Japan; Department of Dentistry, Japan Ground Self-Defense Force Camp, Shinmachi, Japan
| | - Mai Haraguchi-Kitakamae
- Ultrastructure of Hard Tissues, Faculty of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Hotaka Ishizu
- Orthopaedic Surgery, Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - Xuanyu Liu
- Ultrastructure of Hard Tissues, Faculty of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Yan Shi
- Ultrastructure of Hard Tissues, Faculty of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Weisong Li
- Ultrastructure of Hard Tissues, Faculty of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Jiaxin Cui
- Ultrastructure of Hard Tissues, Faculty of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Tomohiro Shimizu
- Orthopaedic Surgery, Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - Norio Amizuka
- Ultrastructure of Hard Tissues, Faculty of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Atsuro Yokoyama
- Oral Functional Prosthodontics, Faculty of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Tomoka Hasegawa
- Ultrastructure of Hard Tissues, Faculty of Dental Medicine, Hokkaido University, Sapporo, Japan.
| | - Kiwamu Sakaguchi
- Oral Functional Prosthodontics, Faculty of Dental Medicine, Hokkaido University, Sapporo, Japan
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Spoladore R, Ciampi CM, Ossola P, Sultana A, Spreafico LP, Farina A, Fragasso G. Heart Failure and Osteoporosis: Shared Challenges in the Aging Population. J Cardiovasc Dev Dis 2025; 12:69. [PMID: 39997503 PMCID: PMC11856909 DOI: 10.3390/jcdd12020069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 01/28/2025] [Accepted: 02/11/2025] [Indexed: 02/26/2025] Open
Abstract
In clinical practice, heart failure (HF) and osteoporosis (OP) are commonly paired conditions. This association is particularly relevant in patients over the age of 50, among whom its prevalence increases dramatically with every decade of life. This can be especially impactful since patient prognosis when facing both conditions is poorer than that of each disease alone. Clinical studies suggest that prior fractures increase the risk for heart failure hospitalization and, conversely, an episode of heart failure increases the risk of subsequent fractures. In other words, the relationship between osteoporosis and heart failure seems to be two-way, meaning that each condition may influence or contribute to the development of the other. However, the details of the pathophysiological relationship between HF and OP have yet to be revealed. The two conditions share multiple pathological mechanisms that seem to be intertwined. Patients affected by OP are more prone to develop HF because of vitamin D deficiency, elevation of parathyroid hormone (PTH) plasma levels, and increased Fibroblast Growth Factor 23 (FGF-23) activity. On the other hand, HF patients are more prone to develop OP and pathological fractures because of low vitamin D level, high PTH, chronic renal failure, alteration of renin-angiotensin-aldosterone system, reduced testosterone level, and metabolic effects derived from commonly used medications. Considering the increasingly aging worldwide population, clinicians can expect to see more often an overlap between these two conditions. Thus, it becomes crucial to recognize how HF and OP mutually influence the patient's clinical condition. Clinicians attending these patients should utilize an integrated approach and, in order to improve prognosis, aim for early diagnosis and treatment initiation. The aim of this paper is to perform a review of the common pathophysiological mechanisms of OP and HF and identify potentially new treatment targets.
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Affiliation(s)
- Roberto Spoladore
- Heart Failure Clinic, Division of Cardiology, Alessandro Manzoni Hospital, ASST Lecco, 23900 Lecco, Italy;
| | - Claudio Mario Ciampi
- Health Science Department, University of Milan Bicocca, 20126 Milan, Italy; (C.M.C.); (P.O.); (A.S.)
| | - Paolo Ossola
- Health Science Department, University of Milan Bicocca, 20126 Milan, Italy; (C.M.C.); (P.O.); (A.S.)
| | - Andrea Sultana
- Health Science Department, University of Milan Bicocca, 20126 Milan, Italy; (C.M.C.); (P.O.); (A.S.)
| | - Luigi Paolo Spreafico
- Orthopedics and Traumatology Unit, San Paolo University Hospital, 20142 Milan, Italy;
| | - Andrea Farina
- Heart Failure Clinic, Division of Cardiology, Alessandro Manzoni Hospital, ASST Lecco, 23900 Lecco, Italy;
| | - Gabriele Fragasso
- Heart Failure Clinic, Division of Cardiology, IRCCS San Raffaele University Hospital, 20132 Milan, Italy;
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Bhandarkar A, Bhavani N, Pavithran PV, Kumar H. Bone Health in Young Adults with Type 1 Diabetes Mellitus in South India. Indian J Endocrinol Metab 2025; 29:49-54. [PMID: 40181854 PMCID: PMC11964363 DOI: 10.4103/ijem.ijem_132_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 11/12/2024] [Accepted: 11/26/2024] [Indexed: 04/05/2025] Open
Abstract
Introduction Patients with type 1 diabetes mellitus (T1DM) have a higher lifetime fracture risk. The rising obesity incidence in T1DM is causing hybrid diabetes. There is scarce data of bone health and body composition in T1DM from India. This South Indian study compared bone health and body composition of patients with T1DM to healthy age- and sex-matched controls. Methods Fifty-one adults with T1DM and 52 healthy controls were enrolled and underwent dual-energy X-ray absorptiometry (DXA) for bone mineral density (BMD) and body composition. Bone turnover markers-C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N pro-peptide (P1NP), parathormone (PTH) and 25 hydroxy-vitamin D levels were measured in patients. Results The mean age of patients with T1DM was 27 years, the median duration of illness was 15 years and the median glycated haemoglobin (HbA1c) was 8%. BMD at the lumbar spine and hip were similar among patients and healthy controls. Patients with T1DM had decreased levels of CTX compared to controls (cases 0.347 (0.233-0.463) ng/mL, controls 0.440 (0.320-0.684) ng/mL, P = 0.005), whereas both had similar levels of P1NP. One-third of patients with T1DM were obese. Patients with T1DM with disease duration more than 10 years showed higher abdomen fat% (<10 years 20.4% [14-39.5], 10-20 years 37.2% [30.1-41.9], >20 years 41.5% [36.4-42.7] P = 0.013) and trunk fat% (<10 years 22.6% [14.8-37.2], 10-20 years 36.7% [30.1-40.5], >20 years 37.6% [33.55-40.5]). Conclusion Young adults with T1DM have normal BMD and low bone resorption markers compared to healthy controls, whereas truncal obesity increases with a longer duration of illness. This may indicate a change in T1DM bone health and body composition characters, probably due to better glycaemic management.
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Affiliation(s)
- Akhila Bhandarkar
- Department of Endocrinology, K. S Hegde Medical Academy, Nitte University, Deralakatte, Nityanandanagar, Mangalore, Karnataka, India
| | - Nisha Bhavani
- Department of Endocrinology, Amrita Institute of Medical Sciences, Ponekkara, Kochi, Kerala, India
| | - Praveen V. Pavithran
- Department of Endocrinology, Amrita Institute of Medical Sciences, Ponekkara, Kochi, Kerala, India
| | - Harish Kumar
- Department of Endocrinology, Amrita Institute of Medical Sciences, Ponekkara, Kochi, Kerala, India
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Park SG, Kim JW, Song JH, Kwon SH, Oh SH, Piao X, Wang Z, Ryu JH, Kim N, Kim OS, Koh JT. The microbial metabolite imidazole propionate dysregulates bone homeostasis by inhibiting AMP-activated protein kinase (AMPK) signaling. Commun Biol 2024; 7:1644. [PMID: 39695168 DOI: 10.1038/s42003-024-07316-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Accepted: 11/25/2024] [Indexed: 12/20/2024] Open
Abstract
Microbial metabolites provide numerous benefits to the human body but can also contribute to diseases such as obesity, diabetes, cancer, and bone disorders. However, the role of imidazole propionate (ImP), a histidine-derived metabolite produced by the intestinal microbiome, in bone metabolism and the development of osteoporosis is still poorly understood. In this study, we investigated the role of ImP and its underlying mechanisms in regulating bone homeostasis. When ImP was administered to 8-week-old mice for 4 weeks, bone loss was observed, along with a decrease in alkaline phosphatase-positive osteoblast cells. Additionally, bone marrow stromal cells (BMSCs) isolated from ImP-treated mice exhibited reduced osteogenic potential. In BMSCs from control mice, ImP treatment inhibited BMP2-induced osteoblast differentiation while promoting adipocyte differentiation. However, ImP had no effect on RANKL-induced osteoclast differentiation or activity in bone marrow macrophages. Mechanistically, ImP treatment increased p38γ phosphorylation and decreased AMPK (T172) phosphorylation in BMSCs. Suppression of p38γ expression using si-p38γ reversed the inhibitory effects of ImP on osteoblast differentiation, with a concurrent increase in AMPK (T172) phosphorylation. Conversely, ImP stimulated adipocyte differentiation by decreasing AMPK (T172) phosphorylation. Treatment with the AMPK agonist metformin significantly reversed the inhibitory effects of ImP on osteoblast differentiation and the promotion of adipocyte differentiation, along with enhanced AMPK (T172) phosphorylation. These findings suggest that the microbial metabolite ImP may disrupt bone homeostasis by stimulating p38γ phosphorylation and inhibiting the AMPK pathway, presenting a potential therapeutic target for managing metabolic bone diseases.
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Affiliation(s)
- Suk-Gyun Park
- Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea
- Hard-Tissue Biointerface Research Center, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea
| | - Jung-Woo Kim
- Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea
- Hard-Tissue Biointerface Research Center, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea
| | - Ju Han Song
- Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea
- Hard-Tissue Biointerface Research Center, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea
| | - Seung-Hee Kwon
- Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea
- Hard-Tissue Biointerface Research Center, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea
| | - Sin-Hye Oh
- Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea
- Hard-Tissue Biointerface Research Center, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea
| | - Xianyu Piao
- Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea
- Hard-Tissue Biointerface Research Center, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea
| | - Zhao Wang
- Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea
- Hard-Tissue Biointerface Research Center, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea
| | - Je-Hwang Ryu
- Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea
- Hard-Tissue Biointerface Research Center, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea
| | - Nacksung Kim
- Hard-Tissue Biointerface Research Center, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea
- Department of Pharmacology, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Ok-Su Kim
- Hard-Tissue Biointerface Research Center, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea
- Department of Periodontology, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea
| | - Jeong-Tae Koh
- Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea.
- Hard-Tissue Biointerface Research Center, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea.
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Roy M, Majid H, Khan P, Sharma N, Kohli S, Islam SU, Vohora D, Nidhi. CTX-1 and TRACP-5b as biomarkers for osteoporosis risk in type 2 diabetes mellitus: a cross-sectional study. J Diabetes Metab Disord 2024; 23:2055-2064. [PMID: 39610562 PMCID: PMC11599675 DOI: 10.1007/s40200-024-01464-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 06/23/2024] [Indexed: 11/30/2024]
Abstract
OBJECTIVE Type 2 diabetes mellitus (T2DM) demonstrates a higher risk of fractures compared to the healthy population. Therefore, the aim of our study is to assess the risk of osteoporosis in T2DM patients. METHODOLOGY A cross-sectional observational study was conducted in T2DM patients. The serum levels of bone resorption markers- carboxy-terminal crosslinked telopeptide of type 1 collagen (CTX-1) and tartrate-resistant acid phosphatase 5b (TRACP-5b) were compared in the T2DM group (n = 43) and the control group (n = 43) and its association with duration of T2DM, HbA1c level, body mass index (BMI), oral hypoglycaemic agents (OHA), and level of functioning was evaluated. RESULTS CTX-1 and TRACP-5b were significantly lower in the T2DM group compared to the control group (p < 0.05). There was no significant correlation between the bone resorption markers and the duration of T2DM and HbA1c levels. However, a significant positive correlation was found between the level of functioning and TRACP-5b level, but no such correlation was observed in T2DM patients. The linear regression model revealed that none of the OHA affected the levels of CTX-1 and TRACP-5b. CONCLUSION The bone resorption markers are not influenced by the duration of T2DM and HbA1c level. However, they were significantly associated with BMI and the level of functionality. However, further research is needed to strengthen the evidence of the association between T2DM and osteoporosis.
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Affiliation(s)
- Madhura Roy
- Department of Translational and Clinical Research, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062 India
| | - Haya Majid
- Department of Translational and Clinical Research, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062 India
| | - Parvej Khan
- Department of Translational and Clinical Research, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062 India
| | - Nikhil Sharma
- Department of Pharmacy Practice, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062 India
| | - Sunil Kohli
- Department of Medicine, Hamdard Institute of Medical Science and Research, New Delhi, 110062 India
| | - Sajad Ul Islam
- Department of Medicine, Hamdard Institute of Medical Science and Research, New Delhi, 110062 India
| | - Divya Vohora
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062 India
| | - Nidhi
- Department of Translational and Clinical Research, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062 India
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Gomez Gramajo F, Rivoira MA, Rodríguez V, Vargas G, Vera Mesones R, Zago MP, Boccaccini AR, Gorustovich A. Lithium-containing 45S5 Bioglass-derived glass-ceramics have antioxidant activity and induce new bone formation in a rat preclinical model of type 1 diabetes mellitus. Biomed Mater 2024; 20:015006. [PMID: 39564894 DOI: 10.1088/1748-605x/ad8c8b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Accepted: 10/29/2024] [Indexed: 11/21/2024]
Abstract
Diabetes mellitus (DM) has been associated with complications that affect the skeletal system, such as alterations in bone repair, osteoporosis, and an increased risk of fractures. In this context, the use of biomaterials able to promote osteogenic differentiation and, at the same time, limit the oxidative stress induced by DM offers a novel perspective to ensure the repair of diabetic bone tissue. Since lithium (Li) has been recently identified as a biologically active ion with osteogenic and antioxidant properties, the localized and controlled release of Li ions from bioactive glass-ceramic materials represents a promising therapeutic alternative for the treatment of bone lesions in DM. Thus, the aim of this study was to evaluate the potential osteogenic and antioxidant effects of glass-ceramic microparticles derived from a 45S5-type bioactive glass (Bioglass) containing (% by weight) 45% SiO2, 24.5% Na2O, 24.5% CaO, and 6% P2O5, in which Na2O was partially substituted by 5% of Li2O (45S5.5Li), in an experimental model of type 1 DM (DM1). The results obtained demonstrate, for the first time, that both 45S5 and 45S5.5Li glass-ceramic microparticles possess antioxidant activity and stimulate bone formationin vivoboth under physiological conditions and under experimental DM1 in rats. In this sense, they would have potential application as inorganic osteogenic agents in different strategies of bone tissue regenerative medicine.
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Affiliation(s)
- Fátima Gomez Gramajo
- Cátedra de Biología del Desarrollo, Facultad de Ciencias Naturales, Universidad Nacional de Salta, Salta, Argentina
| | - María A Rivoira
- Laboratorio 'Dr Fernando Cañas', Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Córdoba, Argentina
| | - Valeria Rodríguez
- Laboratorio 'Dr Fernando Cañas', Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Córdoba, Argentina
| | - Gabriela Vargas
- Cátedra de Biología del Desarrollo, Facultad de Ciencias Naturales, Universidad Nacional de Salta, Salta, Argentina
| | - Rosa Vera Mesones
- Cátedra de Biología del Desarrollo, Facultad de Ciencias Naturales, Universidad Nacional de Salta, Salta, Argentina
| | - María P Zago
- Unidad de Conocimiento Traslacional Hospitalario, CONICET-Hospital Público Materno Infantil, Salta, Argentina
| | - Aldo R Boccaccini
- Institute of Biomaterials, Department of Materials Science and Engineering, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Alejandro Gorustovich
- Laboratorio de Biomateriales, Grupo Interdisciplinario en Materiales-IESIING, Universidad Católica de Salta, grupo vinculado al INTECIN UBA-CONICET, Salta, Argentina
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Huang KA, Choudhary HK, Quesada-Tibbetts KG, Prakash N. Association Between Metabolic Health and Bone Mineral Density Using CT in Hepatocellular Carcinoma Patients Under 65: A Retrospective Chart Review. Cureus 2024; 16:e70835. [PMID: 39493016 PMCID: PMC11531922 DOI: 10.7759/cureus.70835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 10/04/2024] [Indexed: 11/05/2024] Open
Abstract
INTRODUCTION Metabolic conditions such as diabetes, and dyslipidemia are prevalent in the United States (US), serving as potential risk factors for hepatocellular carcinoma (HCC). This study aimed to examine the association between various metabolic markers and Hounsfield Units (HU) from L1 vertebral CT scans as indicators of bone mineral density (BMD) in HCC patients under age 65. METHODS A cross-sectional analysis was conducted on HCC patients under 65. Correlational and regression analyses were used to assess the association of metabolic markers and other health variables with HU scores. RESULTS Race and age were significantly associated with HU scores in multivariate analyses, indicating these factors play a crucial role in bone health among HCC patients. Race showed a positive association, and age showed a negative association with HU scores. Fasting blood glucose had a significant negative correlation with BMD, but this relationship was not significant in univariate regression analysis. No significant correlations were found between HU scores and triglycerides, cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), cholesterol/HDL ratio, LDL/HDL ratio, and hemoglobin A1C (HbA1c) levels. CONCLUSION Traditional metabolic markers may not be strong predictors of osteoporosis in this specific population. Further research with larger, more diverse populations and longitudinal data is necessary to understand better the factors contributing to BMD variations in HCC patients.
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Affiliation(s)
- Kian A Huang
- Radiology, USF Health Morsani College of Medicine, Tampa, USA
| | | | | | - Neelesh Prakash
- Radiology, USF Health Morsani College of Medicine, Tampa, USA
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Tomaszewska E, Dobrowolski P, Muszyński S, Donaldson J, Gołyński M, Zwolska J, Szadkowski M, Osęka M, Mielnik-Błaszczak M, Balicki I. Longitudinal Analysis of Bone Metabolic Markers and Bone Mechanical Properties in STZ-Induced Diabetic Rats. J Clin Med 2024; 13:5595. [PMID: 39337082 PMCID: PMC11433195 DOI: 10.3390/jcm13185595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 09/17/2024] [Accepted: 09/19/2024] [Indexed: 09/30/2024] Open
Abstract
Background: This longitudinal study examined the early effects of type 1 diabetes on bone mechanical properties and metabolic markers in mature rats, focusing on the natural progression of diabetes-induced changes without external treatments. Methods: Forty-eight 8-month-old male Wistar rats were divided into two groups, with one group receiving a single dose of streptozotocin (STZ, 60 mg/kg). Assessments were performed 2, 4, and 8 weeks post-administration, including serum biochemical analyses, bone marker assessments, and mechanical bone tests. The data were analyzed using two-way ANOVA to evaluate the impact of time and treatment. Results: At 2 weeks, diabetic rats showed increased fasting blood glucose (p < 0.001), decreased insulin levels (p = 0.03), and changes in HOMA markers (p < 0.001), liver enzymes (p < 0.001), inflammatory markers (p < 0.001), and bone metabolism markers (osteocalcin (p < 0.001), OPG (p = 0.006), RANKL (p < 0.001), and OPG/RANKL ratio (p < 0.001)), with initial alterations in bone geometry. By week 4, decreased body weight in the diabetic group (p < 0.001) led to further changes in bone geometry and initial differences in mechanical properties. At 8 weeks, significant declines in body (p < 0.001) and bone (p < 0.001) weights were observed, along with further deterioration in bone geometry and mechanical properties. Conclusions: The study highlights the significant impact of STZ-induced diabetes on bone health as early as two weeks post-STZ administration, with marked temporal changes in biochemical markers and mechanical properties.
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Affiliation(s)
- Ewa Tomaszewska
- Department of Animal Physiology, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, 20-950 Lublin, Poland
| | - Piotr Dobrowolski
- Department of Functional Anatomy and Cytobiology, Institute of Biology, Maria Curie Sklodowska University, 20-033 Lublin, Poland
| | - Siemowit Muszyński
- Department of Biophysics, Faculty of Environmental Biology, University of Life Sciences in Lublin, 20-950 Lublin, Poland
| | - Janine Donaldson
- School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Parktown, Johannesburg 2193, South Africa
| | - Marcin Gołyński
- Veterinary Medicine Institute, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University in Toruń, 87-100 Toruń, Poland
| | - Jowita Zwolska
- Department and Clinic of Animal Surgery, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, 20-950 Lublin, Poland
| | - Mateusz Szadkowski
- Department and Clinic of Animal Surgery, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, 20-950 Lublin, Poland
| | - Maciej Osęka
- Hospital Emergency Ward, Specialist Hospital Miedzylesie, 04-749 Warsaw, Poland
| | - Maria Mielnik-Błaszczak
- Chair and Department of Developmental Dentistry, Medical University of Lublin, 20-093 Lublin, Poland
| | - Ireneusz Balicki
- Department and Clinic of Animal Surgery, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, 20-950 Lublin, Poland
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10
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Forner P, Sheu A. Bone Health in Patients With Type 2 Diabetes. J Endocr Soc 2024; 8:bvae112. [PMID: 38887632 PMCID: PMC11181004 DOI: 10.1210/jendso/bvae112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Indexed: 06/20/2024] Open
Abstract
The association between type 2 diabetes mellitus (T2DM) and skeletal fragility is complex, with effects on bone at the cellular, molecular, and biomechanical levels. As a result, people with T2DM, compared to those without, are at increased risk of fracture, despite often having preserved bone mineral density (BMD) on dual-energy x-ray absorptiometry (DXA). Maladaptive skeletal loading and changes in bone architecture (particularly cortical porosity and low cortical volumes, the hallmark of diabetic osteopathy) are not apparent on routine DXA. Alternative imaging modalities, including quantitative computed tomography and trabecular bone score, allow for noninvasive visualization of cortical and trabecular compartments and may be useful in identifying those at risk for fractures. Current fracture risk calculators underestimate fracture risk in T2DM, partly due to their reliance on BMD. As a result, individuals with T2DM, who are at high risk of fracture, may be overlooked for commencement of osteoporosis therapy. Rather, management of skeletal health in T2DM should include consideration of treatment initiation at lower BMD thresholds, the use of adjusted fracture risk calculators, and consideration of metabolic and nonskeletal risk factors. Antidiabetic medications have differing effects on the skeleton and treatment choice should consider the bone impacts in those at risk for fracture. T2DM poses a unique challenge when it comes to assessing bone health and fracture risk. This article discusses the clinical burden and presentation of skeletal disease in T2DM. Two clinical cases are presented to illustrate a clinical approach in assessing and managing fracture risk in these patients.
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Affiliation(s)
- Patrice Forner
- Clinical School, Faculty of Medicine, St Vincent's Hospital, University of New South Wales Sydney, Sydney, NSW 2010, Australia
- Department of Endocrinology and Diabetes, St Vincent's Hospital, Sydney, NSW 2010, Australia
| | - Angela Sheu
- Clinical School, Faculty of Medicine, St Vincent's Hospital, University of New South Wales Sydney, Sydney, NSW 2010, Australia
- Department of Endocrinology and Diabetes, St Vincent's Hospital, Sydney, NSW 2010, Australia
- Skeletal Diseases Program, Garvan Institute of Medical Research, Darlinghurst, NSW 2035, Australia
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11
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Luo K, Peters BA, Moon JY, Xue X, Wang Z, Usyk M, Hanna DB, Landay AL, Schneider MF, Gustafson D, Weber KM, French A, Sharma A, Anastos K, Wang T, Brown T, Clish CB, Kaplan RC, Knight R, Burk RD, Qi Q. Metabolic and inflammatory perturbation of diabetes associated gut dysbiosis in people living with and without HIV infection. Genome Med 2024; 16:59. [PMID: 38643166 PMCID: PMC11032597 DOI: 10.1186/s13073-024-01336-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 04/16/2024] [Indexed: 04/22/2024] Open
Abstract
BACKGROUND Gut dysbiosis has been linked with both HIV infection and diabetes, but its interplay with metabolic and inflammatory responses in diabetes, particularly in the context of HIV infection, remains unclear. METHODS We first conducted a cross-sectional association analysis to characterize the gut microbial, circulating metabolite, and immune/inflammatory protein features associated with diabetes in up to 493 women (~ 146 with prevalent diabetes with 69.9% HIV +) of the Women's Interagency HIV Study. Prospective analyses were then conducted to determine associations of identified metabolites with incident diabetes over 12 years of follow-up in 694 participants (391 women from WIHS and 303 men from the Multicenter AIDS Cohort Study; 166 incident cases were recorded) with and without HIV infection. Mediation analyses were conducted to explore whether gut bacteria-diabetes associations are explained by altered metabolites and proteins. RESULTS Seven gut bacterial genera were identified to be associated with diabetes (FDR-q < 0.1), with positive associations for Shigella, Escherichia, Megasphaera, and Lactobacillus, and inverse associations for Adlercreutzia, Ruminococcus, and Intestinibacter. Importantly, the associations of most species, especially Adlercreutzia and Ruminococcus, were largely independent of antidiabetic medications use. Meanwhile, 18 proteins and 76 metabolites, including 3 microbially derived metabolites (trimethylamine N-oxide, phenylacetylglutamine (PAGln), imidazolepropionic acid (IMP)), 50 lipids (e.g., diradylglycerols (DGs) and triradylglycerols (TGs)) and 23 non-lipid metabolites, were associated with diabetes (FDR-q < 0.1), with the majority showing positive associations and more than half of them (59/76) associated with incident diabetes. In mediation analyses, several proteins, especially interleukin-18 receptor 1 and osteoprotegerin, IMP and PAGln partially mediate the observed bacterial genera-diabetes associations, particularly for those of Adlercreutzia and Escherichia. Many diabetes-associated metabolites and proteins were altered in HIV, but no effect modification on their associations with diabetes was observed by HIV. CONCLUSION Among individuals with and without HIV, multiple gut bacterial genera, blood metabolites, and proinflammatory proteins were associated with diabetes. The observed mediated effects by metabolites and proteins in genera-diabetes associations highlighted the potential involvement of inflammatory and metabolic perturbations in the link between gut dysbiosis and diabetes in the context of HIV infection.
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Affiliation(s)
- Kai Luo
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Brandilyn A Peters
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Jee-Young Moon
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Xiaonan Xue
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Zheng Wang
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Mykhaylo Usyk
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - David B Hanna
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Alan L Landay
- Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA
| | - Michael F Schneider
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Deborah Gustafson
- Department of Neurology, State University of New York-Downstate Medical Center, Brooklyn, NY, USA
| | | | - Audrey French
- Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA
| | - Anjali Sharma
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Kathryn Anastos
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Tao Wang
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Todd Brown
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Clary B Clish
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Robert C Kaplan
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Rob Knight
- Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA, USA
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
- Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA, USA
| | - Robert D Burk
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Qibin Qi
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
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12
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Huang KC, Chuang PY, Yang TY, Tsai YH, Li YY, Chang SF. Diabetic Rats Induced Using a High-Fat Diet and Low-Dose Streptozotocin Treatment Exhibit Gut Microbiota Dysbiosis and Osteoporotic Bone Pathologies. Nutrients 2024; 16:1220. [PMID: 38674910 PMCID: PMC11054352 DOI: 10.3390/nu16081220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 04/11/2024] [Accepted: 04/16/2024] [Indexed: 04/28/2024] Open
Abstract
Type 2 diabetes mellitus (T2DM) presents a challenge for individuals today, affecting their health and life quality. Besides its known complications, T2DM has been found to contribute to bone/mineral abnormalities, thereby increasing the vulnerability to bone fragility/fractures. However, there is still a need for appropriate diagnostic approaches and targeted medications to address T2DM-associated bone diseases. This study aims to investigate the relationship between changes in gut microbiota, T2DM, and osteoporosis. To explore this, a T2DM rat model was induced by combining a high-fat diet and low-dose streptozotocin treatment. Our findings reveal that T2DM rats have lower bone mass and reduced levels of bone turnover markers compared to control rats. We also observe significant alterations in gut microbiota in T2DM rats, characterized by a higher relative abundance of Firmicutes (F) and Proteobacteria (P), but a lower relative abundance of Bacteroidetes (B) at the phylum level. Further analysis indicates a correlation between the F/B ratio and bone turnover levels, as well as between the B/P ratio and HbA1c levels. Additionally, at the genus level, we observe an inverse correlation in the relative abundance of Lachnospiraceae. These findings show promise for the development of new strategies to diagnose and treat T2DM-associated bone diseases.
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Affiliation(s)
- Kuo-Chin Huang
- School of Medicine, Chang Gung University College of Medicine, Taoyuan City 33302, Taiwan; (K.-C.H.); (P.-Y.C.); (T.-Y.Y.); (Y.-H.T.); (Y.-Y.L.)
- Department of Orthopaedic Surgery, Chiayi Chang Gung Memorial Hospital, Chiayi City 61363, Taiwan
| | - Po-Yao Chuang
- School of Medicine, Chang Gung University College of Medicine, Taoyuan City 33302, Taiwan; (K.-C.H.); (P.-Y.C.); (T.-Y.Y.); (Y.-H.T.); (Y.-Y.L.)
- Department of Orthopaedic Surgery, Chiayi Chang Gung Memorial Hospital, Chiayi City 61363, Taiwan
| | - Tien-Yu Yang
- School of Medicine, Chang Gung University College of Medicine, Taoyuan City 33302, Taiwan; (K.-C.H.); (P.-Y.C.); (T.-Y.Y.); (Y.-H.T.); (Y.-Y.L.)
- Department of Orthopaedic Surgery, Chiayi Chang Gung Memorial Hospital, Chiayi City 61363, Taiwan
| | - Yao-Hung Tsai
- School of Medicine, Chang Gung University College of Medicine, Taoyuan City 33302, Taiwan; (K.-C.H.); (P.-Y.C.); (T.-Y.Y.); (Y.-H.T.); (Y.-Y.L.)
- Department of Orthopaedic Surgery, Chiayi Chang Gung Memorial Hospital, Chiayi City 61363, Taiwan
| | - Yen-Yao Li
- School of Medicine, Chang Gung University College of Medicine, Taoyuan City 33302, Taiwan; (K.-C.H.); (P.-Y.C.); (T.-Y.Y.); (Y.-H.T.); (Y.-Y.L.)
- Department of Orthopaedic Surgery, Chiayi Chang Gung Memorial Hospital, Chiayi City 61363, Taiwan
| | - Shun-Fu Chang
- Department of Medical Research and Development, Chiayi Chang Gung Memorial Hospital, Chiayi City 61363, Taiwan
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13
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Takatsu Y, Ohnishi H, Tateyama T, Miyati T. Usefulness of fat-containing agents: an initial study on estimating fat content for magnetic resonance imaging. Phys Eng Sci Med 2024; 47:339-350. [PMID: 38379016 DOI: 10.1007/s13246-023-01372-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 12/11/2023] [Indexed: 02/22/2024]
Abstract
This initial study aimed at testing whether fat-containing agents can be used for the fat mass estimation methods using magnetic resonance imaging (MRI). As an example for clinical application, fat-containing agents (based on soybean oil, 10% and 20%), 100% soybean oil, and saline as reference substances were placed outside the proximal femurs obtained from 14 participants and analyzed by 0.3 T MRI. Fat content was the estimated fat fraction (FF) based on signal intensity (SIeFF, %). The SIeFF values of the femoral bone marrow, including the femoral head, neck, shaft, and trochanter area, were measured. MRI data were compared in terms of bone mineral content (BMC) and bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) in the proximal femur. Twelve pig femurs were also used to confirm the correlation between FF by the DIXON method and SIeFF. According to Pearson's correlation coefficient, the SIeFF and total BMC and BMD data revealed strong and moderate negative correlations in the femoral head (r < - 0.74) and other sites (r = - 0.66 to - 0.45). FF and SIeFF showed a strong correlation (r = 0.96). This study was an initial investigation of a method for estimating fat mass with fat-containing agents and showed the potential for use in MRI. SIeFF and FF showed a strong correlation, and SIeFF and BMD and BMC showed correlation; however, further studies are needed to use SIeFF as a substitute for DXA.
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Affiliation(s)
- Yasuo Takatsu
- Molecular Imaging, School of Medical Sciences, Fujita Health University, 1-98, Dengakugakubo, Kutsukake-Cho, Toyoake, Aichi, 470-1192, Japan.
- Division of Health Sciences, Graduate School of Medical Sciences, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, 920-0942, Japan.
| | - Hiroshi Ohnishi
- Department of Radiology, Geisei Ortho Clinic, 1495-1, Wajikikou, Geisei-Mura, Aki-Gun, Kochi, 781-5701, Japan
| | - Tomoko Tateyama
- Department of Intelligent Information Engineering, School of Medical Sciences, Fujita Health University, 1-98, Dengakugakubo, Kutsukake-Cho, Toyoake, Aichi, 470-1192, Japan
| | - Tosiaki Miyati
- Division of Health Sciences, Graduate School of Medical Sciences, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, 920-0942, Japan
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14
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Wajima CS, Pitol-Palin L, de Souza Batista FR, Dos Santos PH, Matsushita DH, Okamoto R. Morphological and biomechanical characterization of long bones and peri-implant bone repair in type 2 diabetic rats treated with resveratrol. Sci Rep 2024; 14:2860. [PMID: 38310154 PMCID: PMC10838324 DOI: 10.1038/s41598-024-53260-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 01/30/2024] [Indexed: 02/05/2024] Open
Abstract
Type 2 diabetes interferes with bone remodeling mechanisms, requiring studies to reverse this damage, and resveratrol is a polyphenol with rich properties. This study aimed to characterize the long bone morphology and peri-implant biomechanics of normoglycemic and type 2 diabetic animals treated with resveratrol. Thirty-two male Wistar rats were used and divided into normoglycemic and diabetic with or without treatment. They had the installation of implants in the tibia and treatment with oral resveratrol within 45 days. Resveratrol was responsible for weight homeostasis and decreased glycemic levels in rats with type 2 diabetes. The three-point bending testing, resveratrol showed positive effects on the biomechanics of long bones, corroborating a more resistant bone in comparison to untreated diabetics. Micro-ct revealed how bone metabolism is affected by systemic disease, decreasing bone quality. The counter-torque of normoglycemic animals showed superior osseointegration to diabetes, with no differences in the administration of the polyphenol, showing the sovereignty of the deleterious effects of the disease when there is a tissue lesion and an inflammatory picture installed. Overall, resveratrol acted positively in the etiopathogenesis of type 2 diabetes and revealed positive effects on the strength of long bones.
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Affiliation(s)
- Carolina Sayuri Wajima
- Department of Basic Science, Araçatuba School of Dentistry, São Paulo State University (UNESP), Araçatuba, São Paulo, Brazil
| | - Letícia Pitol-Palin
- Department of Diagnosis and Surgery, Araçatuba School of Dentistry, São Paulo State University (UNESP), Araçatuba, São Paulo, Brazil
| | - Fábio Roberto de Souza Batista
- Department of Diagnosis and Surgery, Araçatuba School of Dentistry, São Paulo State University (UNESP), Araçatuba, São Paulo, Brazil
| | | | - Doris Hissako Matsushita
- Department of Basic Science, Araçatuba School of Dentistry, São Paulo State University (UNESP), Araçatuba, São Paulo, Brazil
| | - Roberta Okamoto
- Department of Basic Science, Araçatuba School of Dentistry, São Paulo State University (UNESP), Araçatuba, São Paulo, Brazil.
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15
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Ojurongbe TA, Afolabi HA, Oyekale A, Bashiru KA, Ayelagbe O, Ojurongbe O, Abbasi SA, Adegoke NA. Predictive model for early detection of type 2 diabetes using patients' clinical symptoms, demographic features, and knowledge of diabetes. Health Sci Rep 2024; 7:e1834. [PMID: 38274131 PMCID: PMC10808992 DOI: 10.1002/hsr2.1834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Revised: 12/07/2023] [Accepted: 01/05/2024] [Indexed: 01/27/2024] Open
Abstract
Background and Aims With the global rise in type 2 diabetes, predictive modeling has become crucial for early detection, particularly in populations with low routine medical checkup profiles. This study aimed to develop a predictive model for type 2 diabetes using health check-up data focusing on clinical details, demographic features, biochemical markers, and diabetes knowledge. Methods Data from 444 Nigerian patients were collected and analysed. We used 80% of this data set for training, and the remaining 20% for testing. Multivariable penalized logistic regression was employed to predict the disease onset, incorporating waist-hip ratio (WHR), triglycerides (TG), catalase, and atherogenic indices of plasma (AIP). Results The predictive model demonstrated high accuracy, with an area under the curve of 99% (95% CI = 97%-100%) for the training set and 94% (95% CI = 89%-99%) for the test set. Notably, an increase in WHR (adjusted odds ratio [AOR] = 70.35; 95% CI = 10.04-493.1, p-value < 0.001) and elevated AIP (AOR = 4.55; 95% CI = 1.48-13.95, p-value = 0.008) levels were significantly associated with a higher risk of type 2 diabetes, while higher catalase levels (AOR = 0.33; 95% CI = 0.22-0.49, p < 0.001) correlated with a decreased risk. In contrast, TG levels (AOR = 1.04; 95% CI = 0.40-2.71, p-value = 0.94) were not associated with the disease. Conclusion This study emphasizes the importance of using distinct clinical and biochemical markers for early type 2 diabetes detection in Nigeria, reflecting global trends in diabetes modeling, and highlighting the need for context-specific methods. The development of a web application based on these results aims to facilitate the early identification of individuals at risk, potentially reducing health complications, and improving diabetes management strategies in diverse settings.
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Affiliation(s)
| | | | - Adesola Oyekale
- Department of Chemical PathologyLadoke Akintola University of TechnologyOgbomosoNigeria
| | | | - Olubunmi Ayelagbe
- Department of Chemical PathologyLadoke Akintola University of TechnologyOgbomosoNigeria
| | - Olusola Ojurongbe
- Humboldt Research Hub‐Center for Emerging and Re‐emerging Infectious DiseasesLadoke Akintola University of TechnologyOgbomosoNigeria
- Department of Medical Microbiology and ParasitologyLadoke Akintola University of TechnologyOgbomosoNigeria
| | - Saddam Akber Abbasi
- Statistics Program, Department of Mathematics, Statistics, and Physics, College of Arts and SciencesQatar UniversityDohaQatar
- Statistical Consulting Unit, College of Arts and SciencesQatar UniversityDohaQatar
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16
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Prochaska M, Menezes C, Ko BS, Coe F, Worcester E. Contribution of thick ascending limb and distal convoluted tubule to glucose-induced hypercalciuria in healthy controls. Am J Physiol Renal Physiol 2023; 325:F811-F816. [PMID: 37823200 PMCID: PMC10874680 DOI: 10.1152/ajprenal.00130.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 10/02/2023] [Accepted: 10/02/2023] [Indexed: 10/13/2023] Open
Abstract
Carbohydrates increase kidney stone risk and increase urine calcium and magnesium. We hypothesize that the effects of glucose as an allosteric modulator of calcium-sensing receptors may mediate this effect. Six healthy subjects were on a low-sodium diet before consuming 100 g of glucose beverage. Timed fasting (3) and postglucose (6) urine and blood samples were collected every 30 min. Urine composition and serum markers were measured and microvesicular abundance of tubular transport proteins (NHE3, NKCC2, NCC, and TRPV5) were quantified. Postglucose, serum glucose, and insulin rose rapidly with a parallel increase in calcium and magnesium excretion and no change in fractional excretion of sodium. Both serum parathyroid hormone (PTH) and urine TRPV5 fell in the postglucose periods. The rise in the calcium and magnesium excretion likely occurred primarily in the thick ascending limb where they are both under control of the calcium-sensing receptor. The fall in PTH and TRPV5 support the role of glucose as an allosteric modulator of calcium-sensing receptor.NEW & NOTEWORTHY Sugar increases urine calcium and magnesium as well as kidney stone and bone disease risk. Our study provided new insights into the underlying mechanism as we gave healthy subjects an oral glucose load and used newer tools such as fractional excretion of lithium, serum parathyroid hormone, and microvesicular abundance of tubular transport proteins to characterize the mechanism and identify the thick ascending limb with possible calcium-sensing receptor mediation as a likely contributor to this mechanism.
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Affiliation(s)
- Megan Prochaska
- Department of Medicine, Section of Nephrology, University of Chicago, Chicago, Illinois, United States
| | - Cameron Menezes
- Department of Medicine, Section of Nephrology, University of Chicago, Chicago, Illinois, United States
| | - Benjamin S Ko
- Department of Medicine, Section of Nephrology, University of Chicago, Chicago, Illinois, United States
| | - Fredric Coe
- Department of Medicine, Section of Nephrology, University of Chicago, Chicago, Illinois, United States
| | - Elaine Worcester
- Department of Medicine, Section of Nephrology, University of Chicago, Chicago, Illinois, United States
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17
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Fukaura S, Iwasaki Y. Effect of phosphodiester composition in polyphosphoesters on the inhibition of osteoclastic differentiation of murine bone marrow mononuclear cells. JOURNAL OF BIOMATERIALS SCIENCE. POLYMER EDITION 2023; 34:2319-2331. [PMID: 37530459 DOI: 10.1080/09205063.2023.2244737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 07/22/2023] [Accepted: 07/27/2023] [Indexed: 08/03/2023]
Abstract
Osteoporosis is a common bone disorder characterized by reduced bone density and increased risk of fractures. The modulation of bone cell functions, particularly the inhibition of osteoclastic differentiation, plays a crucial role in osteoporosis treatment. Polyphosphoesters (PPEs) have shown the potential in reducing the function of osteoclast cells, but the effect of their chemical structure on osteoclastic differentiation remains largely unexplored. In this study, we evaluated the effect of PPE's chemical structure on the inhibition of osteoclastic differentiation of murine bone marrow mononuclear cells (BMNCs). PPEs containing phosphotriester and phosphodiester units at varying compositions were synthesized. Cytotoxicity testing confirmed the biocompatibility of the copolymers at concentrations below 0.5 mg/mL. Isolated from long bones, BMNCs were cultured in a differentiation medium supplemented with different PPE concentrations. Osteoclast formation was assessed through tartrate-resistant acid phosphatase and phalloidin staining. A significant decrease in the size of osteoclast cells formed upon BMNC contact with PPEs was observed, with a more pronounced effect observed at higher PPE concentrations. In addition, an increased composition of phosphodiester units in the PPEs yielded a decreased density of differentiated osteoclasts. Furthermore, real-time PCR analysis of major osteoclastic markers provided gene expression data that correlated with microscopic observations, confirming the effect of phosphodiester units in suppressing osteoclast differentiation of BMNCs from the early stages. These findings highlight the potential of PPEs as polymers are capable of modulating bone cell functions through their chemical structures.
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Affiliation(s)
- Sota Fukaura
- Graduate School of Science and Technology, Kansai University, Osaka, Japan
| | - Yasuhiko Iwasaki
- Department of Chemistry and Materials Engineering, Kansai University, Osaka, Japan
- ORDIST, Kansai University, Osaka, Japan
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Zhao R, Xiong C, Zhao Z, Zhang J, Huang Y, Xie Z, Qu X, Luo X, Li Z. Exploration of the Shared Hub Genes and Biological Mechanism in Osteoporosis and Type 2 Diabetes Mellitus based on Machine Learning. Biochem Genet 2023; 61:2531-2547. [PMID: 37140844 DOI: 10.1007/s10528-023-10390-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 04/18/2023] [Indexed: 05/05/2023]
Abstract
A substantial amount of evidence suggests a close relationship between osteoporosis (OP) and Type 2 Diabetes Mellitus (T2DM), but the mechanisms involved remain unknown. Therefore, we conducted this study with the aim of screening for hub genes common to both diseases and conducting a preliminary exploration of common regulatory mechanisms. In the present study, we first screened genes significantly associated with OP and T2DM by the univariate logistic regression algorithm. And then, based on cross-analysis and random forest algorithm, we obtained three hub genes (ACAA2, GATAD2A, and VPS35) and validated the critical roles and predictive performance of the three genes in both diseases by differential expression analysis, receiver operating characteristic (ROC) curves, and genome wide association study (GWAS) analysis. Finally, based on gene set enrichment analysis (GSEA) and the construction of the miRNA-mRNA regulatory network, we conducted a preliminary exploration of the co-regulatory mechanisms of three hub genes in two diseases. In conclusion, this study provides promising biomarkers for predicting and treating both diseases and offers novel directions for exploring the common regulatory mechanisms of both diseases.
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Affiliation(s)
- Runhan Zhao
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Yuzhong, Chongqing, 400016, People's Republic of China
- Orthopedic Laboratory of Chongqing Medical University, Yuzhong, Chongqing, 400016, People's Republic of China
| | - Chuang Xiong
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Yuzhong, Chongqing, 400016, People's Republic of China
- Orthopedic Laboratory of Chongqing Medical University, Yuzhong, Chongqing, 400016, People's Republic of China
| | - Zenghui Zhao
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Yuzhong, Chongqing, 400016, People's Republic of China
- Orthopedic Laboratory of Chongqing Medical University, Yuzhong, Chongqing, 400016, People's Republic of China
| | - Jun Zhang
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Yuzhong, Chongqing, 400016, People's Republic of China
- Orthopedic Laboratory of Chongqing Medical University, Yuzhong, Chongqing, 400016, People's Republic of China
| | - Yanran Huang
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Yuzhong, Chongqing, 400016, People's Republic of China
- Orthopedic Laboratory of Chongqing Medical University, Yuzhong, Chongqing, 400016, People's Republic of China
| | - Zhou Xie
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Yuzhong, Chongqing, 400016, People's Republic of China
- Orthopedic Laboratory of Chongqing Medical University, Yuzhong, Chongqing, 400016, People's Republic of China
| | - Xiao Qu
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Yuzhong, Chongqing, 400016, People's Republic of China
- Orthopedic Laboratory of Chongqing Medical University, Yuzhong, Chongqing, 400016, People's Republic of China
| | - Xiaoji Luo
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Yuzhong, Chongqing, 400016, People's Republic of China.
- Orthopedic Laboratory of Chongqing Medical University, Yuzhong, Chongqing, 400016, People's Republic of China.
| | - Zefang Li
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Yuzhong, Chongqing, 400016, People's Republic of China.
- Department of Orthopedics, Qianjiang Central Hospital of Chongqing, Qianjiang, Chongqing, 409000, People's Republic of China.
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Ye Y, Yi X, Zhang Y, Xu G, Yu M, Qu X. Association between renal function and bone mineral density in patients with type 2 diabetes mellitus. Heliyon 2023; 9:e15967. [PMID: 37215877 PMCID: PMC10195895 DOI: 10.1016/j.heliyon.2023.e15967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 04/25/2023] [Accepted: 04/27/2023] [Indexed: 05/24/2023] Open
Abstract
Background This study evaluated the association between renal function, assessed by serum creatinine and estimated glomerular filtration rate (eGFR) according to the Cockcroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) equations, and bone mineral density (BMD) in Chinese patients with type 2 diabetes mellitus (T2DM). Methods 1322 patients with T2DM were included, and their basic clinical information, serum biochemical tests, and BMD at the total hip and femur neck were collected. Multivariate adjusted linear regression, smooth curve fitting and a piecewise linear regression model were used to analyze linear and nonlinear associations. Age, BMI, drinking, smoking, systolic blood pressure and diastolic blood pressure, FBG, HbA1C, course of diabetes, hsCRP, TC, TG, HDL-C, LDL-C, Ca, P, PTH, ALP, OC, P1NP, β-CTX and 25(OH)D were adjusted. Results After adjusting the variables, no correlation between eGFR CG and eGFR MDRD and femur neck BMD was observed in women, men, or the total population. The eGFR CG and eGFR MDRD had a significant positive association with total hip BMD in men and the total population with T2DM. With a 10-unit decrease in eGFR CG, total hip BMD reduced by 0.012 g/cm2 in men and 0.010 g/cm2 the total population. Total hip BMD reduced by 0.014 g/cm2 in men and 0.022 g/cm2 in the total population with a 10-unit decrease in eGFR MDRD. There was no correlation between eGFR CG or eGFR MDRD and total hip BMD in female participants. Conclusion Impaired renal function was associated with decreased total hip BMD in men and the total population with T2DM. No associated between renal function with femur neck BMD was observed.
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Affiliation(s)
- Yangli Ye
- Department of Endocrinology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xilu Yi
- Department of Endocrinology, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Endocrinology and Metabolism, Central Hospital of Songjiang District, Shanghai, China
| | - Yao Zhang
- Department of Endocrinology, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Infectious Disease, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Guiping Xu
- Department of Endocrinology, Zhongshan Hospital, Fudan University, Shanghai, China
- VIP Clinical Department, Fujian Provincial Hospital, Fuzhou, China
| | - Mingxiang Yu
- Department of Endocrinology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xinhua Qu
- Department of Bone and Joint Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Mukherjee S, Pal R, Bhadada SK, Kaur A, Rastogi A. Bone mineral density and its predictors in a cohort of adults with type 1 diabetes attending a tertiary care institute in North India. Int J Diabetes Dev Ctries 2023. [DOI: 10.1007/s13410-023-01185-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/12/2023] Open
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21
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Muacevic A, Adler JR, Konstantopoulos P, Driva TS, Kontos A, Papagianni E, Kourkoulis S, Dimitroulis D, Perrea DN, Vlamis J. Effects of Incretin Pathway Elements on Bone Properties. Cureus 2023; 15:e33656. [PMID: 36643078 PMCID: PMC9833274 DOI: 10.7759/cureus.33656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/11/2023] [Indexed: 01/13/2023] Open
Abstract
Introduction The effects of incretin-based drugs, such as receptor agonists of glucagon-like peptide-1 and inhibitors of dipeptidyl peptidase-4, on bone metabolism are not completely clear yet. The aim of this study is to compare the effects of glucagon-like peptide-1 and inhibitors of dipeptidyl peptidase-4 on the bone to see how different elements of the incretin pathway affect bone quality in terms of biomechanical properties, bone turnover, and mineral properties. Materials and methods Forty 10-week-old Wistar rats were divided into four groups: a control group, a control diabetic group, a diabetic group treated with sitagliptin, and a diabetic group treated with exenatide. Type 2 diabetes was simulated by dietary manipulation in addition to low-dose streptozotocin, and then two different incretin-based drugs were administered. The rats were sacrificed after five weeks of therapeutic treatment. Their serum was analyzed with the enzyme-linked immunosorbent assay (ELISA) method for basic bone turnover markers, and their right femur was subjected to a three-point bending test. Finally, Hematoxylin & Eosin staining, in addition to Raman spectroscopy, were employed to access the collagen and mineral properties of the bone. Results Both incretin-based drugs reduced osteoclast function; however, they were not able to restore osteoblastic function to normal. The net effect on bone strength was surprising: bone elasticity was restored by the antidiabetic treatment, but bone strength deteriorated. Exenatide had a slightly more pronounced effect, which, although not significant, points to the direction that dipeptidyl peptidase-4 (DPP4) may be a linking factor between reduced osteoclastic function and reduced bone formation, as suggested by the literature. Conclusion DPP4 receptors seem to be one of the links between reduced osteoclast function and reduced bone remodeling, so DPP4 inhibition can be more detrimental to the bone than glucagon-like peptide-1 (GLP-1) receptor agonists.
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Gua C, Li T, Wang J. Causal association between heart failure and bone mineral density: Insights from a two-sample bidirectional Mendelian randomization study. Genomics 2022; 114:110522. [PMID: 36400116 DOI: 10.1016/j.ygeno.2022.110522] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 10/06/2022] [Accepted: 11/06/2022] [Indexed: 11/17/2022]
Abstract
In recent times, the association between HF and BMD has attracted enormous interest in the scientific community. However, published epidemiological observational studies on the relationship between HF and BMD remain inconclusive. Herein, we evaluated from the analytical perspective a two-sample bidirectional MR study to analyze the causal association between HF and BMD using a summary-level GWAS Catalog. To select instrumental SNPs strongly associated with exposure, we took a series of rigorous quality control steps at the time of analysis. The causal MR assessment of HF on the risk of BMD was performed first and then in the opposite direction. To make the conclusions more reliable and robust, the fixed-effects IVW, weighted median-based method, MR-Egger, simple mode and weighted mode were utilized. A maximum likelihood model was also used if necessary. MR-Egger regression, IVW "leave-one-out" sensitivity analysis, MR-PRESSO, MR-Egger intercept test and Cochran's Q statistic methods were used to assess heterogeneity and pleiotropy. Our MR studies supported a meaningful causal association between HF and TB-BMD (IVW: OR = 0.78, 95% CI: 0.68-0.87, p = 0.00588). At the same time, we did not find a significant causal relationship between HF and FA-BMD, FN-BMD or LS-BMD. No significant causal relationships between BMD and HF were observed. This bidirectional MR analysis suggested a causal association of HF with only low TB-BMD, while the reverse causality hypothesis was not found. Studies of the prevention and treatment of total bone mineral density decline in patients with heart failure need to be performed.
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Affiliation(s)
- Chaojun Gua
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China
| | - Tiejun Li
- Department of General Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China
| | - Jiahe Wang
- Department of General Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China.
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Karsenty G, Khosla S. The crosstalk between bone remodeling and energy metabolism: A translational perspective. Cell Metab 2022; 34:805-817. [PMID: 35545088 PMCID: PMC9535690 DOI: 10.1016/j.cmet.2022.04.010] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/30/2022] [Accepted: 04/20/2022] [Indexed: 12/15/2022]
Abstract
Genetics in model organisms has progressively broken down walls that previously separated different disciplines of biology. One example of this holistic evolution is the recognition of the complex relationship that exists between the control of bone mass (bone remodeling) and energy metabolism in mammals. Numerous hormones orchestrate this crosstalk. In particular, the study of the leptin-mediated regulation of bone mass has not only revealed the existence of a central control of bone mass but has also led to the realization that sympathetic innervation is a major regulator of bone remodeling. This happened at a time when the use of drugs aiming at treating osteoporosis, the most frequent bone disease, has dwindled. This review will highlight the main aspects of the leptin-mediated regulation of bone mass and how this led to the realization that β-blockers, which block the effects of the sympathetic nervous system, may be a viable option to prevent osteoporosis.
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Affiliation(s)
- Gerard Karsenty
- Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
| | - Sundeep Khosla
- Kogod Center of Aging and Division of Endocrinology and Metabolism, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
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24
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Kurban S, Selver Eklioglu B, Selver MB. Investigation of the relationship between serum sclerostin and dickkopf-1 protein levels with bone turnover in children and adolescents with type-1 diabetes mellitus. J Pediatr Endocrinol Metab 2022; 35:673-679. [PMID: 35411762 DOI: 10.1515/jpem-2022-0001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Accepted: 03/15/2022] [Indexed: 12/24/2022]
Abstract
OBJECTIVES Diabetes mellitus (DM) is widely known to have a detrimental effect on bone health and is associated with increased fracture risk. Recently, the Wnt/beta-catenin signaling pathway and its inhibitors sclerostin and dickkopf-1 (Dkk-1) were found to be involved in the control of bone mass. The present study aimed to measure serum sclerostin and Dkk-1 protein levels in children and adolescents with type-1 DM and compare with other bone turnover markers and bone mineral density (BMD). METHODS This study was performed on 40 children and adolescents with type-I DM and 40 healthy children and adolescents. Anthropometric measurements and pubertal examination were done. In addition to laboratory analysis, dickkopf-1, sclerostin, cross-linked N-telopeptides of type I collagen (NTx), bone alkaline phosphatase (bALP), and osteocalcin levels were studied. BMD of the participants was measured by calcaneus ultrasonography. RESULTS Dickkopf-1 levels of the children and adolescents with type-1 DM were significantly higher, vitamin D, NTx, osteocalcin, and phosphorus levels were significantly lower than those of the controls (p<0.001). Fasting blood glucose, HbA1c, and insulin were significantly higher in the type 1 DM group (p<0.01). CONCLUSIONS Both bone remodeling and its compensatory mechanism bone loss are lower in children and adolescents with type-1 DM than in the controls. Also, higher levels of Dkk-1 play a role in decreased bone turnover in these patients. Since Dkk-1 and sclerostin seem to take a role in treating metabolic bone diseases in the future, we believe that our findings are significant in this respective.
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Affiliation(s)
- Sevil Kurban
- Department of Biochemistry, Necmettin Erbakan University Faculty of Medicine, Konya, Turkey
| | - Beray Selver Eklioglu
- Division of Pediatric Endocrinology, Necmettin Erbakan University Faculty of Medicine, Konya, Turkey
| | - Muhammed Burak Selver
- Department of Pediatrics, Necmettin Erbakan University Faculty of Medicine, Konya, Turkey
- Istanbul University, Institute of Health Sciences and Institute of Child Health Social Pediatrics PhD Program, Istanbul, Turkey
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25
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Sheu A, Greenfield JR, White CP, Center JR. Assessment and treatment of osteoporosis and fractures in type 2 diabetes. Trends Endocrinol Metab 2022; 33:333-344. [PMID: 35307247 DOI: 10.1016/j.tem.2022.02.006] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/01/2022] [Accepted: 02/22/2022] [Indexed: 01/10/2023]
Abstract
There is substantial, and growing, evidence that type 2 diabetes (T2D) is associated with skeletal fragility, despite often preserved bone mineral density. As post-fracture outcomes, including mortality, are worse in people with T2D, bone management should be carefully considered in this highly vulnerable group. However, current fracture risk calculators inadequately predict fracture risk in T2D, and dedicated randomised controlled trials identifying optimal management in patients with T2D are lacking, raising questions about the ideal assessment and treatment of bone health in these people. We synthesise the current literature on evaluating bone measurements in T2D and summarise the evidence for safety and efficacy of both T2D and anti-osteoporosis medications in relation to bone health in these patients.
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Affiliation(s)
- Angela Sheu
- Bone Biology Division, Garvan Institute of Medical Research, Sydney, Australia; Clinical School, St Vincent's Hospital, Faculty of Medicine, University of New South Wales Sydney, Sydney, Australia; Department of Endocrinology and Diabetes, St Vincent's Hospital, Sydney, Australia.
| | - Jerry R Greenfield
- Clinical School, St Vincent's Hospital, Faculty of Medicine, University of New South Wales Sydney, Sydney, Australia; Department of Endocrinology and Diabetes, St Vincent's Hospital, Sydney, Australia; Diabetes and Metabolism, Garvan Institute of Medical Research, Sydney, Australia
| | - Christopher P White
- Clinical School, Prince of Wales Hospital, Faculty of Medicine, University of New South Wales Sydney, Sydney, Australia; Department of Endocrinology and Metabolism, Prince of Wales Hospital, Sydney, Australia
| | - Jacqueline R Center
- Bone Biology Division, Garvan Institute of Medical Research, Sydney, Australia; Clinical School, St Vincent's Hospital, Faculty of Medicine, University of New South Wales Sydney, Sydney, Australia; Department of Endocrinology and Diabetes, St Vincent's Hospital, Sydney, Australia
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26
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Wu X, Gong H, Hu X, Shi P, Cen H, Li C. Effect of verapamil on bone mass, microstructure and mechanical properties in type 2 diabetes mellitus rats. BMC Musculoskelet Disord 2022; 23:363. [PMID: 35436905 PMCID: PMC9016927 DOI: 10.1186/s12891-022-05294-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 04/04/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Verapamil was mainly used to treat hypertension, cardiovascular disease, inflammation and improve blood glucose in patients with diabetes, but its effects on bone mass, microstructure and mechanical properties were unclear. This study described the effects of verapamil on bone mass, microstructure, macro and nano mechanical properties in type 2 diabetic rats. METHODS Rat models of type 2 diabetes were treated with verapamil at doses of 4, 12, 24 and 48 mg/kg/day by gavage respectively, twice a day. After 12 weeks, all rats were sacrificed under general anesthesia. Blood glucose, blood lipid, renal function and biochemical markers of bone metabolism were obtained by serum analysis, Micro-CT scanning was used to assess the microstructure parameters of cancellous bone of femoral head, three-point bending test was used to measure maximum load and elastic modulus of femoral shaft, and nano-indentation tests were used to measure indentation moduli and hardnesses of longitudinal cortical bone in femoral shaft, longitudinal and transverse cancellous bones in femoral head. RESULTS Compared with T2DM group, transverse indentation moduli of cancellous bones in VER 24 group, longitudinal and transverse indentation moduli and hardnesses of cancellous bones in VER 48 group were significantly increased (p < 0.05). Furthermore, the effects of verapamil on blood glucoses, microstructures and mechanical properties in type 2 diabetic rats were dependent on drug dose. Starting from verapamil dose of 12 mg/kg/day, with dose increasing, the concentrations of P1NP, BMD, BV/TV, Tb. Th, Tb. N, maximum loads, elastic moduli, indentation moduli and hardnesses of femurs in rats in treatment group increased gradually, the concentrations of CTX-1 decreased gradually, but these parameters did not return to the level of the corresponding parameters of normal rats. Verapamil (48 mg/kg/day) had the best therapeutic effect. CONCLUSION Verapamil treatment (24, 48 mg/kg/day) significantly affected nano mechanical properties of the femurs, and tended to improve bone microstructures and macro mechanical properties of the femurs, which provided guidance for the selection of verapamil dose in the treatment of type 2 diabetic patients.
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Affiliation(s)
- Xiaodan Wu
- Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, China
| | - He Gong
- Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, China.
| | - Xiaorong Hu
- Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, China
| | - Peipei Shi
- Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, China
| | - Haipeng Cen
- Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, China
| | - Chenchen Li
- Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, China
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Liu YD, Liu JF, Liu B. N,N-Dimethylformamide inhibits high glucose-induced osteoporosis via attenuating MAPK and NF-κB signalling. Bone Joint Res 2022; 11:200-209. [PMID: 35369730 PMCID: PMC9057521 DOI: 10.1302/2046-3758.114.bjr-2020-0308.r2] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Aims The role of N,N-dimethylformamide (DMF) in diabetes-induced osteoporosis (DM-OS) progression remains unclear. Here, we aimed to explore the effect of DMF on DM-OS development. Methods Diabetic models of mice, RAW 264.7 cells, and bone marrow macrophages (BMMs) were established by streptozotocin stimulation, high glucose treatment, and receptor activator of nuclear factor-κB ligand (RANKL) treatment, respectively. The effects of DMF on DM-OS development in these models were examined by micro-CT analysis, haematoxylin and eosin (H&E) staining, osteoclast differentiation of RAW 264.7 cells and BMMs, H&E and tartrate-resistant acid phosphatase (TRAP) staining, enzyme-linked immunosorbent assay (ELISA) of TRAP5b and c-terminal telopeptides of type 1 (CTX1) analyses, reactive oxygen species (ROS) analysis, quantitative reverse transcription polymerase chain reaction (qRT-PCR), Cell Counting Kit-8 (CCK-8) assay, and Western blot. Results The established diabetic mice were more sensitive to ovariectomy (OVX)-induced osteoporosis, and DMF treatment inhibited the sensitivity. OVX-treated diabetic mice exhibited higher TRAP5b and c-terminal telopeptides of type 1 (CTX1) levels, and DMF treatment inhibited the enhancement. DMF reduced RAW 264.7 cell viability. Glucose treatment enhanced the levels of TRAP5b, cathepsin K, Atp6v0d2, and H+-ATPase, ROS, while DMF reversed this phenotype. The glucose-increased protein levels were inhibited by DMF in cells treated with RANKL. The expression levels of antioxidant enzymes Gclc, Gclm, Ho-1, and Nqo1 were upregulated by DMF. DMF attenuated high glucose-caused osteoclast differentiation by targeting mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signalling in BMMs. Conclusion DMF inhibits high glucose-induced osteoporosis by targeting MAPK and NF-κB signalling. Cite this article: Bone Joint Res 2022;11(4):200–209.
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Affiliation(s)
- Ya Dong Liu
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun, China
| | - Jian Feng Liu
- Department of Hand Surgery, The First Hospital of Jilin University, Changchun, China
| | - Bin Liu
- Department of Hand Surgery, The First Hospital of Jilin University, Changchun, China
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Cifuentes-Mendiola SE, Solis-Suarez DL, Martínez-Dávalos A, Godínez-Victoria M, García-Hernández AL. CD4 + T-cell activation of bone marrow causes bone fragility and insulin resistance in type 2 diabetes. Bone 2022; 155:116292. [PMID: 34896656 DOI: 10.1016/j.bone.2021.116292] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 12/02/2021] [Accepted: 12/03/2021] [Indexed: 12/14/2022]
Abstract
Type 2 diabetes mellitus (T2DM) causes an increased risk of bone fractures. However, the pathophysiology of diabetic bone fragility is not completely understood. It has been proposed that an inflammatory microenvironment in bone could be a major mechanism by inducing uncontrolled bone resorption, inadequate bone formation and consequently more porous bones. We propose that activated T-cells in the bone marrow cause a pro-inflammatory microenvironment in bone, and cause bone fragility in T2DM. We induced T2DM in C57BL/6 male mice through a hypercaloric diet rich in carbohydrates and low doses of streptozocin. In T2DM mice we inhibited systemic activation of T-cells with a fusion protein between the extracellular domain of Cytotoxic T-Lymphocyte Antigen 4 and the Fc domain of human immunoglobulin G (CTLA4-Ig). We analysed the effects of T2DM or CTLA4-Ig in lymphocyte cell subsets and antigen-presenting cells in peripheral blood and femoral bone marrow; and their effect on the metabolic phenotype, blood and bone cytokine concentration, femoral bone microarchitecture and biomechanical properties, and the number of osteoblast-like cells in the femoral endosteum. We performed a Pearson multiple correlation analysis between all variables in order to understand the global mechanism. Results demonstrated that CTLA4-Ig decreased the number of activated CD4+ T-cells in the femoral bone marrow and consequently decreased TNF-α and RANK-L concentration in bone, notably improved femoral bone microarchitecture and biomechanical properties, increased the number of osteoblast-like cells, and reduces osteoclastic activity compared to T2DM mice that did not receive the inhibitor. Interestingly, we observed that blood glucose levels and insulin resistance may be related to the increase in activated CD4+ T-cells in the bone marrow. We conclude that bone marrow activated CD4+ T-cells cause poor bone quality and insulin resistance in T2DM.
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Affiliation(s)
- S E Cifuentes-Mendiola
- Laboratory of Dental Research, Section of Osteoimmunology and Oral Immunology, FES Iztacala, National Autonomous University of Mexico, A. Jiménez Gallardo SN, San Sebastián Xhala, Cuautitlán Izcalli, Estado de México, CP 54714, Mexico; Postgraduate in Biological Sciences, National Autonomous University of Mexico, Mexico, Mexico
| | - D L Solis-Suarez
- Laboratory of Dental Research, Section of Osteoimmunology and Oral Immunology, FES Iztacala, National Autonomous University of Mexico, A. Jiménez Gallardo SN, San Sebastián Xhala, Cuautitlán Izcalli, Estado de México, CP 54714, Mexico
| | - A Martínez-Dávalos
- Physics Institute, National Autonomous University of Mexico, Circuito de la Investigación Científica, Ciudad Universitaria, 04510 México City, Mexico
| | - M Godínez-Victoria
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico, Mexico
| | - A L García-Hernández
- Laboratory of Dental Research, Section of Osteoimmunology and Oral Immunology, FES Iztacala, National Autonomous University of Mexico, A. Jiménez Gallardo SN, San Sebastián Xhala, Cuautitlán Izcalli, Estado de México, CP 54714, Mexico.
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Ruiz-Esteves KN, Teysir J, Schatoff D, Yu EW, Burnett-Bowie SAM. Disparities in osteoporosis care among postmenopausal women in the United States. Maturitas 2022; 156:25-29. [PMID: 35033230 DOI: 10.1016/j.maturitas.2021.10.010] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 10/06/2021] [Accepted: 10/19/2021] [Indexed: 12/20/2022]
Abstract
Osteoporosis and fragility fractures result in significant morbidity and mortality and contribute to substantial healthcare costs. Despite being a treatable disease, osteoporosis remains both underdiagnosed and undertreated in the US general population, with significant disparities in care between non-White and White women. These disparities are evident from screening to post-fracture treatment. Non-White women are less likely to be screened for osteoporosis, to be prescribed pharmacotherapy, or to receive treatment post-fracture; furthermore, the mortality rate after fracture is higher in non-White women. Given existing diagnostic and treatment disparities, additional studies and interventions are needed to optimize the bone health of Asian, Black, Hispanic, and Native American women, and to reduce morbidity and mortality from osteoporosis and fragility fractures.
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Affiliation(s)
- Karina N Ruiz-Esteves
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 50 Blossom Street, Thier 1051, Boston, MA 02114-2696, USA
| | - Jimmitti Teysir
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 50 Blossom Street, Thier 1051, Boston, MA 02114-2696, USA
| | - Daria Schatoff
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 50 Blossom Street, Thier 1051, Boston, MA 02114-2696, USA
| | - Elaine W Yu
- Endocrine Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Sherri-Ann M Burnett-Bowie
- Endocrine Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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Cifuentes‑Mendiola S, Moreno‑Fierros L, González‑Alva P, García‑Hernández A. Docosahexaenoic acid improves altered mineralization proteins, the decreased quality of hydroxyapatite crystals and suppresses oxidative stress induced by high glucose. Exp Ther Med 2022; 23:235. [PMID: 35222712 PMCID: PMC8815046 DOI: 10.3892/etm.2022.11160] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 12/30/2021] [Indexed: 11/23/2022] Open
Abstract
Patients with type 2 diabetes mellitus (DM2) experience an increased risk of fractures and a variety of bone pathologies, such as osteoporosis. The suggested mechanisms of increased fracture risk in DM2 include chronic hyperglycaemia, which provokes oxidative stress, alters bone matrix, and decreases the quality of hydroxyapatite crystals. Docosahexaenoic acid (DHA), an omega-3 fatty acid, can increase bone formation, reduce bone loss, and it possesses antioxidant/anti-inflammatory properties. The present study aimed to determine the effect of DHA on altered osteoblast mineralisation and increased reactive oxygen species (ROS) induced by high glucose concentrations. A human osteoblast cell line was treated with 5.5 mM glucose (NG) or 24 mM glucose (HG), alone or in combination with 10 or 20 µM DHA. The collagen type 1 (Col1) scaffold, the expression of osteocalcin (OCN) and bone sialoprotein type-II (BSP-II), the alkaline phosphatase (ALP) specific activity, the mineral quality, the production of ROS and the mRNA expression of nuclear factor erythroid 2-related factor-2 (NRF2) were analysed. Osteoblasts cultured in HG and treated with either DHA concentration displayed an improved distribution of the Col1 scaffold, increased OCN and BSP-II expression, increased NRF2 mRNA, decreased ALP activity, carbonate substitution and reduced ROS production compared with osteoblasts cultured in HG alone. DHA counteracts the adverse effects of HG on bone mineral matrix quality and reduces oxidative stress, possibly by increasing the expression of NRF2.
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Affiliation(s)
- Saúl Cifuentes‑Mendiola
- Laboratory of Dental Research, Section of Osteoimmunology and Oral Immunology, FES Iztacala, National Autonomous University of Mexico, San Sebastián Xhala, Cuautitlán Izcalli 54714, Mexico
| | - Leticia Moreno‑Fierros
- Laboratory of Mucosal Immunity, FES Iztacala, National Autonomous University of Mexico, Los Reyes Iztacala, Tlalnepantla 54090, Mexico
| | - Patricia González‑Alva
- Laboratory of Tissue Bioengineering, Dentistry Faculty, National Autonomous University of Mexico, University City, Mexico City 04510, Mexico
| | - Ana García‑Hernández
- Laboratory of Dental Research, Section of Osteoimmunology and Oral Immunology, FES Iztacala, National Autonomous University of Mexico, San Sebastián Xhala, Cuautitlán Izcalli 54714, Mexico
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Chen HH, Petty LE, North KE, McCormick JB, Fisher-Hoch SP, Gamazon ER, Below JE. OUP accepted manuscript. Hum Mol Genet 2022; 31:3191-3205. [PMID: 35157052 PMCID: PMC9476627 DOI: 10.1093/hmg/ddac039] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 01/17/2022] [Accepted: 01/18/2022] [Indexed: 11/17/2022] Open
Abstract
Type 2 diabetes is a complex, systemic disease affected by both genetic and environmental factors. Previous research has identified genetic variants associated with type 2 diabetes risk; however, gene regulatory changes underlying progression to metabolic dysfunction are still largely unknown. We investigated RNA expression changes that occur during diabetes progression using a two-stage approach. In our discovery stage, we compared changes in gene expression using two longitudinally collected blood samples from subjects whose fasting blood glucose transitioned to a level consistent with type 2 diabetes diagnosis between the time points against those who did not with a novel analytical network approach. Our network methodology identified 17 networks, one of which was significantly associated with transition status. This 822-gene network harbors many genes novel to the type 2 diabetes literature but is also significantly enriched for genes previously associated with type 2 diabetes. In the validation stage, we queried associations of genetically determined expression with diabetes-related traits in a large biobank with linked electronic health records. We observed a significant enrichment of genes in our identified network whose genetically determined expression is associated with type 2 diabetes and other metabolic traits and validated 31 genes that are not near previously reported type 2 diabetes loci. Finally, we provide additional functional support, which suggests that the genes in this network are regulated by enhancers that operate in human pancreatic islet cells. We present an innovative and systematic approach that identified and validated key gene expression changes associated with type 2 diabetes transition status and demonstrated their translational relevance in a large clinical resource.
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Affiliation(s)
- Hung-Hsin Chen
- Vanderbilt Genetics Institute and Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Lauren E Petty
- Vanderbilt Genetics Institute and Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Kari E North
- Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Joseph B McCormick
- The University of Texas Health Science Center at Houston (UTHealth) School of Public Health, Brownsville, TX 78520, USA
| | - Susan P Fisher-Hoch
- The University of Texas Health Science Center at Houston (UTHealth) School of Public Health, Brownsville, TX 78520, USA
| | - Eric R Gamazon
- Vanderbilt Genetics Institute and Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Clare Hall, University of Cambridge, Cambridgeshire, UK
| | - Jennifer E Below
- To whom correspondence should be addressed. Tel: +1-615-343-1655;
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Peng S, Gao Y, Shi S, Zhao D, Cao H, Fu T, Cai X, Xiao J. LncRNA-AK137033 inhibits the osteogenic potential of adipose-derived stem cells in diabetic osteoporosis by regulating Wnt signaling pathway via DNA methylation. Cell Prolif 2022; 55:e13174. [PMID: 34953002 PMCID: PMC8780896 DOI: 10.1111/cpr.13174] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/06/2021] [Accepted: 12/09/2021] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVES Bone tissue engineering based on adipose-derived stem cells (ASCs) is expected to become a new treatment for diabetic osteoporosis (DOP) patients with bone defects. However, compared with control ASCs (CON-ASCs), osteogenic potential of DOP-ASCs is decreased, which increased the difficulty of bone reconstruction in DOP patients. Moreover, the cause of the poor osteogenesis of ASCs in a hyperglycemic microenvironment has not been elucidated. Therefore, this study explored the molecular mechanism of the decline in the osteogenic potential of DOP-ASCs from the perspective of epigenetics to provide a possible therapeutic target for bone repair in DOP patients with bone defects. MATERIALS AND METHODS An animal model of DOP was established in mice. CON-ASCs and DOP-ASCs were isolated from CON and DOP mice, respectively. AK137033 small interfering RNA (SiRNA) and an AK137033 overexpression plasmid were used to regulate the expression of AK137033 in CON-ASCs and DOP-ASCs in vitro. Lentiviruses that carried shRNA-AK137033 or AK137033 cDNA were used to knockdown or overexpress AK137033, respectively, in CON-ASCs and DOP-ASCs in vivo. Hematoxylin and eosin (H&E), Masson's, alizarin red, and alkaline phosphatase (ALP) staining, micro-computed tomography (Micro-CT), flow cytometry, qPCR, western blotting, immunofluorescence, and bisulfite-specific PCR (BSP) were used to analyze the functional changes of ASCs. RESULTS The DOP mouse model was established successfully. Compared with CON-ASCs, AK137033 expression, the DNA methylation level of the sFrp2 promoter region, Wnt signaling pathway markers, and the osteogenic differentiation potential were decreased in DOP-ASCs. In vitro experiments showed that AK137033 silencing inhibited the Wnt signaling pathway and osteogenic ability of CON-ASCs by reducing the DNA methylation level in the sFrp2 promoter region. Additionally, overexpression of AK137033 in DOP-ASCs rescued these changes caused by DOP. Moreover, the same results were obtained in vivo. CONCLUSIONS LncRNA-AK137033 inhibits the osteogenic potential of DOP-ASCs by regulating the Wnt signaling pathway via modulating the DNA methylation level in the sFrp2 promoter region. This study provides an important reference to find new targets for the treatment of bone defects in DOP patients.
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Affiliation(s)
- Shuanglin Peng
- Department of Oral ImplantologyThe Affiliated Stomatology Hospital of Southwest Medical UniversityLuzhouChina
- State Key Laboratory of Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
- National Key Clinical SpecialtyThe Affiliated Hospital of Southwest Medical UniversityLuzhouChina
| | - Yujin Gao
- Department of Oral ImplantologyThe Affiliated Stomatology Hospital of Southwest Medical UniversityLuzhouChina
- Orofacial Reconstruction and Regeneration LaboratoryThe Affiliated Stomatology Hospital of Southwest Medical UniversityLuzhouChina
- Department of Oral and Maxillofacial SurgeryThe Affiliated Stomatology Hospital of Southwest Medical UniversityLuzhouChina
| | - Sirong Shi
- State Key Laboratory of Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Dan Zhao
- State Key Laboratory of Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Huayue Cao
- Department of Oral ImplantologyThe Affiliated Stomatology Hospital of Southwest Medical UniversityLuzhouChina
- National Key Clinical SpecialtyThe Affiliated Hospital of Southwest Medical UniversityLuzhouChina
- Department of Oral and Maxillofacial SurgeryThe Affiliated Stomatology Hospital of Southwest Medical UniversityLuzhouChina
| | - Ting Fu
- Department of Oral ImplantologyThe Affiliated Stomatology Hospital of Southwest Medical UniversityLuzhouChina
- National Key Clinical SpecialtyThe Affiliated Hospital of Southwest Medical UniversityLuzhouChina
- Department of Oral and Maxillofacial SurgeryThe Affiliated Stomatology Hospital of Southwest Medical UniversityLuzhouChina
| | - Xiaoxiao Cai
- State Key Laboratory of Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Jingang Xiao
- Department of Oral ImplantologyThe Affiliated Stomatology Hospital of Southwest Medical UniversityLuzhouChina
- National Key Clinical SpecialtyThe Affiliated Hospital of Southwest Medical UniversityLuzhouChina
- Orofacial Reconstruction and Regeneration LaboratoryThe Affiliated Stomatology Hospital of Southwest Medical UniversityLuzhouChina
- Department of Oral and Maxillofacial SurgeryThe Affiliated Stomatology Hospital of Southwest Medical UniversityLuzhouChina
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Abstract
Osteocytes, former osteoblasts encapsulated by mineralized bone matrix, are far from being passive and metabolically inactive bone cells. Instead, osteocytes are multifunctional and dynamic cells capable of integrating hormonal and mechanical signals and transmitting them to effector cells in bone and in distant tissues. Osteocytes are a major source of molecules that regulate bone homeostasis by integrating both mechanical cues and hormonal signals that coordinate the differentiation and function of osteoclasts and osteoblasts. Osteocyte function is altered in both rare and common bone diseases, suggesting that osteocyte dysfunction is directly involved in the pathophysiology of several disorders affecting the skeleton. Advances in osteocyte biology initiated the development of novel therapeutics interfering with osteocyte-secreted molecules. Moreover, osteocytes are targets and key distributors of biological signals mediating the beneficial effects of several bone therapeutics used in the clinic. Here we review the most recent discoveries in osteocyte biology demonstrating that osteocytes regulate bone homeostasis and bone marrow fat via paracrine signaling, influence body composition and energy metabolism via endocrine signaling, and contribute to the damaging effects of diabetes mellitus and hematologic and metastatic cancers in the skeleton.
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Affiliation(s)
- Jesus Delgado-Calle
- 1Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas,2Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Teresita Bellido
- 1Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas,2Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas,3Central Arkansas Veterans Healthcare System, Little Rock, Arkansas
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Zhao Z, Lu Y, Wang H, Gu X, Zhu L, Guo H, Li N. ALK7 Inhibition Protects Osteoblast Cells Against High Glucoseinduced ROS Production via Nrf2/HO-1 Signaling Pathway. Curr Mol Med 2022; 22:354-364. [PMID: 34126915 DOI: 10.2174/1566524021666210614144337] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 03/17/2021] [Accepted: 03/18/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Some studies demonstrated that under high-glucose (HG) condition, osteoblasts develop oxidative stress, which will impair their normal functions. The effects of activin receptor-like kinase 7 (ALK7) silencing on HG-induced osteoblasts remained unclear. OBJECTIVE The aim of this study was to explore the effect of ALK7 on HG-induced osteoblasts. METHODS MC3T3-E1 cells were treated with different concentrations of HG (0, 50, 100, 200 and 300mg/dL), and the cell viability was detected using cell counting kit-8 (CCK-8). HG-treated MC3T3-E1 cells were transfected with siALK7 or ALK7 overexpression plasmid or siNrf2, and then the viability and apoptosis were detected by CCK-8 and flow cytometry. The levels of Reactive Oxygen Species (ROS), collagen I and calcification nodule were determined by oxidative stress kits, Enzyme-linked immunosorbent assay and Alizarin red staining. The expressions of NF-E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and osteoblast-associated genes were determined by quantitative real-time PCR (qRT-PCR) and Western blot. RESULTS Cell viability was reduced with HG treatment. Silencing ALK7 inhibited the effect of HG on increasing cell apoptosis and ROS production, reduced cell viability, mineralized nodules, and downregulated collagen I and osteoblast-associated genes expression in MC3T3-E1 cells. ALK7 silencing activated the Nrf2/HO-1 signaling pathway by affecting expressions of HO-1 and Nrf2. ALK7 overexpression had the opposite effects. In addition, siNrf2 partially reversed the effects of ALK7 silencing on HG-induced MC3T3-E1 cells. CONCLUSION ALK7 silencing protected osteoblasts under HG condition possibly through activating the Nrf2/HO-1 pathway.
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Affiliation(s)
- Zhen Zhao
- Department of Geriatrics, Beijing Friendship Hospital, Capital Medical University, Xicheng District, Beijing, 100050, China
| | - Yu Lu
- Department of Geriatrics, Beijing Friendship Hospital, Capital Medical University, Xicheng District, Beijing, 100050, China
| | - Huan Wang
- Department of Geriatrics, Beijing Friendship Hospital, Capital Medical University, Xicheng District, Beijing, 100050, China
| | - Xiang Gu
- Department of Geriatrics, Beijing Friendship Hospital, Capital Medical University, Xicheng District, Beijing, 100050, China
| | - Luting Zhu
- Department of Geriatrics, Beijing Friendship Hospital, Capital Medical University, Xicheng District, Beijing, 100050, China
| | - Hong Guo
- Department of Geriatrics, Beijing Friendship Hospital, Capital Medical University, Xicheng District, Beijing, 100050, China
| | - Nan Li
- Department of Endocrinology, The Second Medical Center & National Clinical Research Center, Chinese PLA General Hospital, Haidian District, Beijing, 100853, China
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Jeddi S, Yousefzadeh N, Kashfi K, Ghasemi A. Role of nitric oxide in type 1 diabetes-induced osteoporosis. Biochem Pharmacol 2021; 197:114888. [PMID: 34968494 DOI: 10.1016/j.bcp.2021.114888] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 12/09/2021] [Accepted: 12/09/2021] [Indexed: 12/18/2022]
Abstract
Type 1 diabetes (T1D)-induced osteoporosis is characterized by decreased bone mineral density, bone quality, rate of bone healing, bone formation, and increased bone resorption. Patients with T1D have a 2-7-fold higher risk of osteoporotic fracture. The mechanisms leading to increased risk of osteoporotic fracture in T1D include insulin deficiency, hyperglycemia, insulin resistance, lower insulin-like growth factor-1, hyperglycemia-induced oxidative stress, and inflammation. In addition, a higher probability of falling, kidney dysfunction, weakened vision, and neuropathy indirectly increase the risk of osteoporotic fracture in T1D patients. Decreased nitric oxide (NO) bioavailability contributes to the pathophysiology of T1D-induced osteoporotic fracture. This review discusses the role of NO in osteoblast-mediated bone formation and osteoclast-mediated bone resorption in T1D. In addition, the mechanisms involved in reduced NO bioavailability and activity in type 1 diabetic bones as well as NO-based therapy for T1D-induced osteoporosis are summarized. Available data indicates that lower NO bioavailability in diabetic bones is due to disruption of phosphatidylinositol 3‑kinase/protein kinase B/endothelial NO synthases and NO/cyclic guanosine monophosphate/protein kinase G signaling pathways. Thus, NO bioavailability may be boosted directly or indirectly by NO donors. As NO donors with NO-like effects in the bone, inorganic nitrate and nitrite can potentially be used as novel therapeutic agents for T1D-induced osteoporosis. Inorganic nitrites and nitrates can decrease the risk for osteoporotic fracture probably directly by decreasing osteoclast activity, decreasing fat accumulation in the marrow cavity, increasing osteoblast activity, and increasing bone perfusion or indirectly, by improving hyperglycemia, insulin resistance, and reducing body weight.
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Affiliation(s)
- Sajad Jeddi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nasibeh Yousefzadeh
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Khosrow Kashfi
- Department of Molecular, Cellular, and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, NY, USA.
| | - Asghar Ghasemi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Stocker R, Shaw J, Taylor GS, Witham MD, West DJ. EXercise to Prevent frailty and Loss Of independence in insulin treated older people with DiabetEs (EXPLODE): protocol for a feasibility randomised controlled trial (RCT). BMJ Open 2021; 11:e048932. [PMID: 34880011 PMCID: PMC8655574 DOI: 10.1136/bmjopen-2021-048932] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
INTRODUCTION There are 3.9 million people in the UK with diabetes. Sarcopenia, increased frailty and loss of independence are often unappreciated complications of diabetes. Resistance exercise shows promise in reducing these complications in older adult diabetes patients. The aim of this feasibility randomised controlled trial is to (1) characterise the physical function, cardiovascular health and the health and well-being of older adults with mild frailty with/without diabetes treated with insulin, (2) to understand the feasibility and acceptability of a 4-week resistance exercise training programme in improving these parameters for those with diabetes and (3) to test the feasibility of recruiting and randomising the diabetic participant group to a trial of resistance training. METHODS AND ANALYSIS Thirty adults aged ≥60 years with insulin-treated diabetes mellitus (type 1 or 2), and 30 without, all with mild frailty (3-4 on the Rockwood Frailty Scale) will be recruited. All will complete blood, cardiovascular and physical function testing. Only the diabetic group will then proceed into the trial itself. They will be randomised 1:1 to a 4-week semisupervised resistance training programme, designed to increase muscle mass and strength, or to usual care, defined as their regular physical activity, for 4 weeks. This group will then repeat testing. Primary outcomes include recruitment rate, attrition rate, intervention fidelity and acceptability, and adherence to the training programme. A subset of participants will be interviewed before and after the training programme to understand experiences of resistance training, impact on health and living with diabetes (where relevant) as they have aged. Analyses will include descriptive statistics and qualitative thematic analysis. ETHICS AND DISSEMINATION The North East-Newcastle and North Tyneside 2 Research Ethics Committee (20/NE/0178) approved the study. Outputs will include feasibility data to support funding applications for a future definitive trial, conference and patient and public involvement presentations, and peer-reviewed publications. TRIAL REGISTRATION NUMBER ISRCTN13193281.
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Affiliation(s)
- Rachel Stocker
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - James Shaw
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Guy S Taylor
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Miles D Witham
- NIHR Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, UK
| | - Daniel J West
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
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Ha J, Jeong C, Han KD, Lim Y, Kim MK, Kwon HS, Song KH, Kang MI, Baek KH. Comparison of fracture risk between type 1 and type 2 diabetes: a comprehensive real-world data. Osteoporos Int 2021; 32:2543-2553. [PMID: 34333678 DOI: 10.1007/s00198-021-06032-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 06/11/2021] [Indexed: 12/24/2022]
Abstract
UNLABELLED Population-based cohort study of 6,548,784 Korean subjects demonstrates that the risk of fracture was higher in patients with diabetes than in nondiabetic subjects. Furthermore, patients with type 1 diabetes were associated with a higher risk of fracture than patients with type 2 diabetes for all measurement sites. INTRODUCTION Diabetes mellitus is associated with increased fracture risk. Although the pathophysiologic effect on bone metabolism differs according to the type of diabetes, a higher risk of fracture in patients with diabetes than in nondiabetic patients has been consistently demonstrated. Considering the ever-increasing number of patients with diabetes, we aimed to provide updated information on whether this phenomenon remains valid in real-world settings by using large-scale population datasets. METHODS We conducted a retrospective longitudinal study using data from the Korean National Health Insurance Service dataset of preventive health check-ups between January 2009 and December 2016. The hazard ratios were calculated for any fracture, vertebral fracture, and hip fracture and were analyzed according to the presence and type of diabetes. Among 10,585,818 subjects, 6,548,784 were eligible for the analysis (2418 patients with type 1 diabetes mellitus [T1DM] and 506,208 patients with type 2 diabetes mellitus [T2DM]). RESULTS The mean follow-up duration (in years) was 7.0 ± 1.3 for subjects without diabetes, 6.4 ± 2.0 for those with T1DM, and 6.7 ± 1.7 for T2DM. Patients with T1DM had a higher incidence rate for all types of fractures per 1000 person-years. The fully adjusted hazard ratios (HRs) for any fracture, vertebral fracture, and hip fracture were higher in T1DM than in T2DM (1.37 [95% confidence interval (CI): 1.23-1.52] for any fracture, 1.33 [95% CI: 1.09-1.63] for vertebral fracture, and 1.99 [95% CI: 1.56-2.53] for hip fracture). CONCLUSIONS In this large-scale population analysis, diabetes was associated with a higher risk of all types of fractures. Patients with T1DM had a higher risk of fracture than those with T2DM for all measurement sites, and hip fractures had the highest risk. Therefore, fracture prevention training for patients with diabetes is advisable.
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Affiliation(s)
- J Ha
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - C Jeong
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - K-D Han
- Department of Statistics and Actuarial Science, Soongsil University, Seoul, Republic of Korea
| | - Y Lim
- Division of General Internal Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - M K Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - H-S Kwon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - K-H Song
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - M I Kang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - K-H Baek
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
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Ben-Joseph R, Luboshitz B, Heffez Ayzenfeld R, Twito O. Post-hip fracture rehabilitation outcomes of diabetic and non-diabetic elderly patients. Ann Med 2021; 53:2298-2304. [PMID: 34856850 PMCID: PMC8648020 DOI: 10.1080/07853890.2021.2009555] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 11/17/2021] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND Although patients with diabetes mellitus (DM) are at higher risk of hip fracture, data regarding the effect of DM on rehabilitation outcomes are limited. METHODS A retrospective single-centre study was conducted comparing elderly diabetic and non-diabetic patients with recent hip fracture, admitted to geriatric rehabilitation, 2014-2019. The functional independence measure (FIM) was used to assess physical and cognitive function. Delta-FIM was calculated by subtracting admission FIM from discharge FIM. One-year mortality, hospitalizations and fractures were assessed. RESULTS Six-hundred-thirty elderly patients, post-hip fracture were included, mean age 83 ± 7 years, 70.5% (444) women. Among them, 193 (30.6%) had type 2 DM, HbA1c 6.6 ± 1.25%. They were younger (81.4 vs. 84.3 years, p < .01) and had more co-morbidities including hypertension, chronic kidney disease, ischaemic heart disease and cerebrovascular disease. Baseline cognitive and motor scores were similar between groups. Delta motor-FIM was similar between diabetics and non-diabetics (15.56 ± 8.95 and 14.78 ± 8.79, respectively, p = .35). Multivariate regression analysis showed motor-FIM improvement was associated with higher BMI, male sex, and younger age, but not with DM. Cognitive FIM did not change significantly during rehabilitation in either group. Similar rates of patients were discharged to nursing care facilities. There was no difference in 1-year hospitalization or fracture rates. One-year, all-cause mortality was higher among diabetic patients (10.9 vs. 6.6%, respectively, p = .07). After adjusting for covariates, DM was associated with higher mortality risk (odds ratio = 2.78, 95% CI [1.28, 6.04], p = .01). CONCLUSIONS Patients with well-controlled DM have similar post-hip fracture rehabilitation potential compared with non-diabetics, despite more co-morbidities. These results support resource allocation for post-hip fracture rehabilitation among patients with DM. The higher 1-year all-cause mortality in patients with DM reinforces the need for close follow-up and control of co-morbidities in this population.
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Affiliation(s)
- Ronen Ben-Joseph
- Department of Geriatric Rehabilitation, Meir Medical Center, Kfar Saba, Israel
| | - Barak Luboshitz
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | | | - Orit Twito
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Institute of Endocrinology, Meir Medical Center, Kfar Saba, Israel
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Zhang M, Yang B, Peng S, Xiao J. Metformin Rescues the Impaired Osteogenesis Differentiation Ability of Rat Adipose-Derived Stem Cells in High Glucose by Activating Autophagy. Stem Cells Dev 2021; 30:1017-1027. [PMID: 34486387 DOI: 10.1089/scd.2021.0181] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The incidence and morbidity of diabetes osteoporosis (DOP) are increasing with each passing year. Patients with DOP have a higher risk of bone fracture and poor healing of bone defects, which make a poor quality of their life. Bone tissue engineering based on autologous adipose-derived stem cells (ASCs) transplantation develops as an effective technique to achieve tissue regeneration for patients with bone defects. With the purpose of promoting auto-ASCs transplantation, this research project explored the effect of metformin on the osteogenic differentiation of ASCs under a high-glucose culture environment. In this study, we found that 40 mM high glucose inhibited the physiological function of ASCs, including cell proliferation, migration, and osteogenic differentiation. Indicators of osteogenic differentiation were all downregulated by 40 mM high glucose, including alkaline phosphatase activity, runt-related transcription factor 2, and osteopontin gene expression, and Wnt signaling pathway. At the same time, the cell autophagy makers BECLIN1 and microtubule-associated protein 1 light chain 3 (LC3 I/II) were decreased. While 0.1 mM metformin upregulated the expression of BECLIN1 and LC3 I/II gene and inhibited the expression of mammalian target of rapamycin (mTOR) and GSK3β, it contributed to reverse the osteogenesis inhibition of ASCs caused by high glucose. When 3-methyladenine was used to block the activity of metformin, metformin could not exert its protective effect on ASCs. All the findings elaborated the regulatory mechanism of metformin in the high-glucose microenvironment to protect the osteogenic differentiation ability of ASCs. Metformin plays an active role in promoting the osteogenic differentiation of ASCs with DOP, and it may contribute to the application of ASCs transplantation for bone regeneration in DOP.
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Affiliation(s)
- Maorui Zhang
- Department of Oral Implantology, The Affiliated Stomatology Hospital of Southwest Medical University, Luzhou, People's Republic of China.,Oral & Maxillofacial Reconstruction and Regeneration Laboratory, The Affiliated Stomatology Hospital of Southwest Medical University, Luzhou, People's Republic of China.,Division of Oral Health Sciences, Department of Fixed Prosthodontics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Bo Yang
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, People's Republic of China
| | - Shuanglin Peng
- Department of Oral Implantology, The Affiliated Stomatology Hospital of Southwest Medical University, Luzhou, People's Republic of China.,Oral & Maxillofacial Reconstruction and Regeneration Laboratory, The Affiliated Stomatology Hospital of Southwest Medical University, Luzhou, People's Republic of China
| | - Jingang Xiao
- Department of Oral Implantology, The Affiliated Stomatology Hospital of Southwest Medical University, Luzhou, People's Republic of China.,Oral & Maxillofacial Reconstruction and Regeneration Laboratory, The Affiliated Stomatology Hospital of Southwest Medical University, Luzhou, People's Republic of China
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Syversen U, Mosti MP, Mynarek IM, Vedal TSJ, Aasarød K, Basso T, Reseland JE, Thorsby PM, Asvold BO, Eriksen EF, Stunes AK. Evidence of impaired bone quality in men with type 1 diabetes: a cross-sectional study. Endocr Connect 2021; 10:955-964. [PMID: 34289447 PMCID: PMC8428087 DOI: 10.1530/ec-21-0193] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 07/21/2021] [Indexed: 11/12/2022]
Abstract
OBJECTIVE Type 1 diabetes (T1D) is associated with substantial fracture risk. Bone mineral density (BMD) is, however, only modestly reduced, suggesting impaired bone microarchitecture and/or bone material properties. Yet, the skeletal abnormalities have not been uncovered. Men with T1D seem to experience a more pronounced bone loss than their female counterparts. Hence, we aimed to examine different aspects of bone quality in men with T1D. DESIGN AND METHODS In this cross-sectional study, men with T1D and healthy male controls were enrolled. BMD (femoral neck, total hip, lumbar spine, whole body) and spine trabecular bone score (TBS) were measured by dual x-ray absorptiometry, and bone material strength index (BMSi) was measured by in vivo impact microindentation. HbA1c and bone turnover markers were analyzed. RESULTS Altogether, 33 men with T1D (43 ± 12 years) and 28 healthy male controls (42 ± 12 years) were included. Subjects with T1D exhibited lower whole-body BMD than controls (P = 0.04). TBS and BMSi were attenuated in men with T1D vs controls (P = 0.016 and P = 0.004, respectively), and T1D subjects also had a lower bone turnover. The bone parameters did not differ between subjects with or without diabetic complications. Duration of disease correlated negatively with femoral neck BMD but not with TBS or BMSi. CONCLUSIONS This study revealed compromised bone material strength and microarchitecture in men with T1D. Moreover, our data confirm previous studies which found a modest decrease in BMD and low bone turnover in subjects with T1D. Accordingly, bone should be recognized as a target of diabetic complications.
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Affiliation(s)
- Unni Syversen
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Department of Endocrinology, Trondheim University Hospital (St Olavs Hospital), Trondheim, Norway
- Correspondence should be addressed to U Syversen:
| | - Mats Peder Mosti
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Medical Clinic, Trondheim University Hospital (St Olavs Hospital), Trondheim, Norway
| | - Ida Maria Mynarek
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Trude Seselie Jahr Vedal
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Kristin Aasarød
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Department of Gastroenterology, Trondheim University Hospital (St Olavs Hospital), Trondheim, Norway
| | - Trude Basso
- Department of Orthopedics, Trondheim University Hospital (St Olavs Hospital), Trondheim, Norway
| | | | - Per Medbøe Thorsby
- Hormone Laboratory, Department of Medical Biochemistry, Oslo University Hospital, Aker, Oslo, Norway
| | - Bjorn O Asvold
- Department of Endocrinology, Trondheim University Hospital (St Olavs Hospital), Trondheim, Norway
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Trondheim, Norway
| | | | - Astrid Kamilla Stunes
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Medical Clinic, Trondheim University Hospital (St Olavs Hospital), Trondheim, Norway
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Swimming Training Does Not Affect the Recovery of Femoral Midshaft Structural and Mechanical Properties in Growing Diabetic Rats Treated with Insulin. Life (Basel) 2021; 11:life11080786. [PMID: 34440530 PMCID: PMC8398667 DOI: 10.3390/life11080786] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 07/18/2021] [Accepted: 07/23/2021] [Indexed: 12/04/2022] Open
Abstract
Background: The effects of swimming training associated with insulin treatment on the cortical bone health in young rats with severe type 1 diabetes remain unclear, although there is evidence of such effects on the cancellous bone. This study examined the effects of swimming training combined with insulin therapy on the femoral midshaft structural and mechanical properties in growing rats with type 1 diabetes. Methods: Male Wistar rats were divided into six groups (n = 10): control sedentary, control exercise, diabetic sedentary, diabetic exercise, diabetic sedentary plus insulin and diabetic exercise plus insulin. Diabetic rats received an injection (60 mg/kg body weight) of streptozotocin (STZ). Exercised animals underwent a swimming program for eight weeks. Results: Diabetes induced by STZ decreased the bone mineral content (BMC) and density (BMD), and cortical thickness and maximum load and tenacity in the femoral midshaft. Insulin treatment partially counteracted the damages induced by diabetes on BMC, BMD and cortical thickness and tenacity. Swimming training did not affect the femoral structural and mechanical properties in diabetic rats. The combination of treatments did not potentiate the insulin effects. In conclusion, swimming training does not affect the benefits of insulin treatment on the femoral midshaft structural and mechanical properties in growing rats with severe type 1 diabetes.
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Palui R, Pramanik S, Mondal S, Ray S. Critical review of bone health, fracture risk and management of bone fragility in diabetes mellitus. World J Diabetes 2021; 12:706-729. [PMID: 34168723 PMCID: PMC8192255 DOI: 10.4239/wjd.v12.i6.706] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 04/08/2021] [Accepted: 04/29/2021] [Indexed: 02/06/2023] Open
Abstract
The risk of fracture is increased in both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). However, in contrast to the former, patients with T2DM usually possess higher bone mineral density. Thus, there is a considerable difference in the pathophysiological basis of poor bone health between the two types of diabetes. Impaired bone strength due to poor bone microarchitecture and low bone turnover along with increased risk of fall are among the major factors behind elevated fracture risk. Moreover, some antidiabetic medications further enhance the fragility of the bone. On the other hand, antiosteoporosis medications can affect the glucose homeostasis in these patients. It is also difficult to predict the fracture risk in these patients because conventional tools such as bone mineral density and Fracture Risk Assessment Tool score assessment can underestimate the risk. Evidence-based recommendations for risk evaluation and management of poor bone health in diabetes are sparse in the literature. With the advancement in imaging technology, newer modalities are available to evaluate the bone quality and risk assessment in patients with diabetes. The purpose of this review is to explore the pathophysiology behind poor bone health in diabetic patients. Approach to the fracture risk evaluation in both T1DM and T2DM as well as the pragmatic use and efficacy of the available treatment options have been discussed in depth.
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Affiliation(s)
- Rajan Palui
- Department of Endocrinology, The Mission Hospital, Durgapur 713212, West Bengal, India
| | - Subhodip Pramanik
- Department of Endocrinology, Neotia Getwel Healthcare Centre, Siliguri 734010, West Bengal, India
| | - Sunetra Mondal
- Department of Endocrinology, Institute of Post Graduate Medical Education and Research (IPGMER), Kolkata 700020, West Bengal, India
| | - Sayantan Ray
- Department of Endocrinology, Medica Superspeciality Hospital and Medica Clinic, Kolkata 700099, West Bengal, India
- Department of Endocrinology, Jagannath Gupta Institute of Medical Sciences and Hospital, Kolkata 700137, West Bengal, India
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43
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Zhu Q, Xu J, Zhou M, Lian X, Xu J, Shi J. Association between type 1 diabetes mellitus and reduced bone mineral density in children: a meta-analysis. Osteoporos Int 2021; 32:1143-1152. [PMID: 33404757 DOI: 10.1007/s00198-020-05715-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 10/23/2020] [Indexed: 12/16/2022]
Abstract
UNLABELLED In this meta-analysis, we analyzed 9 cross-sectional studies for an association between type 1 diabetes mellitus (T1DM) and bone mineral density (BMD) in children. We found that BMD Z-scores were significantly reduced in children with T1DM. INTRODUCTION Recent cross-sectional studies have examined how T1DM influences bone health in children and adolescents, but the relationship between T1DM and BMD remains unclear due to conflicting reports. METHODS In this meta-analysis, we systematically searched PubMed, Cochrane library, and Web of Science databases (for publications through March 12, 2020), and calculated weight mean difference (WMD) along with 95% confidence intervals (CI) using a random-effects model. Heterogeneity was evaluated using the I2 method. The Newcastle-Ottawa Scale was used to assess the quality of the included studies. RESULTS Data were analyzed from 9 eligible studies, including a total of 1522 children and adolescents. These data were tested for an association between T1DM and BMD. This analysis found a significant decrease in BMD Z-score in the whole body (pooled WMD, - 0.47, 95% CI, - 0.92 to - 0.02, I2 = 80.2%) and lumbar spine (pooled WMD, - 0.41, 95% CI, - 0.69 to - 0.12, I2 = 80.3%) in children and adolescents with T1DM, which was consistent in published studies from Asia and South America, but inconsistent in the North America and Europe. Importantly, the differences in BMD Z-scores were independent of age, level of glucose control (HbA1c), and prepubertal stage. Sensitivity analyses did not modify these findings. Funnel plot and the Egger test did not reveal significant publication bias. CONCLUSION This meta-analysis suggests that T1DM may play a role in decreasing BMD Z-scores in the whole body and lumbar spine in children.
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Affiliation(s)
- Q Zhu
- Department of Translational Medicine Platform, Affiliated Hospital of Hangzhou Normal University, No. 126 Wenzhou Road, Gongshu District, Zhejiang Province, 310000, Hangzhou, China
| | - J Xu
- Medical College of Hangzhou Normal University, No.2318 Yuhangtang Road, Yuhang District, Zhejiang Province, 311121, Hangzhou, China
| | - M Zhou
- Department of Neurology, Affiliated Hospital of Hangzhou Normal University, No. 126 Wenzhou Road, Gongshu District, Zhejiang Province, 310000, Hangzhou, China
| | - X Lian
- Metabolic Disease Center and Department of Orthopedics, Affiliated Hospital of Hangzhou Normal University, No. 126 Wenzhou Road, Gongshu District, Zhejiang Province, 310000, Hangzhou, China
| | - J Xu
- Department of Endocrinology, Xinqiao Hospital, Army Medical University, No. 83 Xinqiaozheng road, Shaping District, Chongqing, 400037, China.
| | - J Shi
- Department of Hepatology & Infectious Diseases, Affiliated Hospital of Hangzhou Normal University, No. 126 Wenzhou Road, Gongshu District, Zhejiang Province, 310000, Hangzhou, China.
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Dixit M, Liu Z, Poudel SB, Yildirim G, Zhang YZ, Mehta S, Murik O, Altarescu G, Kobayashi Y, Shimizu E, Schaffler MB, Yakar S. Skeletal Response to Insulin in the Naturally Occurring Type 1 Diabetes Mellitus Mouse Model. JBMR Plus 2021; 5:e10483. [PMID: 33977201 PMCID: PMC8101621 DOI: 10.1002/jbm4.10483] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 01/03/2021] [Accepted: 02/24/2021] [Indexed: 11/24/2022] Open
Abstract
Patients with type 1 diabetes mellitus (T1DM) exhibit reduced BMD and significant increases in fracture risk. Changes in BMD are attributed to blunted osteoblast activity and inhibited bone remodeling, but these cannot fully explain the impaired bone integrity in T1DM. The goal of this study was to determine the cellular mechanisms that contribute to impaired bone morphology and composition in T1DM. Nonobese diabetic (NOD) mice were used, along with μCT, histomorphometry, histology, Raman spectroscopy, and RNAseq analyses of several skeletal sites in response to naturally occurring hyperglycemia and insulin treatment. The bone volume in the axial skeleton was found to be severely reduced in diabetic NOD mice and was not completely resolved with insulin treatment. Decreased bone volume in diabetic mice was associated with increased sclerostin expression in osteocytes and attenuation of bone formation indices without changes in bone resorption. In the face of blunted bone remodeling, decreases in the mineral:matrix ratio were found in cortical bones of diabetic mice by Raman microspectroscopy, suggesting that T1DM did not affect the bone mineralization process per se, but rather resulted in microenvironmental alterations that favored mineral loss. Bone transcriptome analysis indicated metabolic shifts in response to T1DM. Dysregulation of genes involved in fatty acid oxidation, transport, and synthesis was found in diabetic NOD mice. Specifically, pyruvate dehydrogenase kinase isoenzyme 4 and glucose transporter 1 levels were increased, whereas phosphorylated-AKT levels were significantly reduced in diabetic NOD mice. In conclusion, in addition to the blunted bone formation, osteoblasts and osteocytes undergo metabolic shifts in response to T1DM that may alter the microenvironment and contribute to mineral loss from the bone matrix. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Manisha Dixit
- David B. Kriser Dental Center, Department of Molecular PathobiologyNew York University College of Dentistry New YorkNew YorkNYUSA
| | - Zhongbo Liu
- David B. Kriser Dental Center, Department of Molecular PathobiologyNew York University College of Dentistry New YorkNew YorkNYUSA
| | - Sher Bahadur Poudel
- David B. Kriser Dental Center, Department of Molecular PathobiologyNew York University College of Dentistry New YorkNew YorkNYUSA
| | - Gozde Yildirim
- David B. Kriser Dental Center, Department of Molecular PathobiologyNew York University College of Dentistry New YorkNew YorkNYUSA
| | - Yanjiao Zhang Zhang
- David B. Kriser Dental Center, Department of Molecular PathobiologyNew York University College of Dentistry New YorkNew YorkNYUSA
| | - Shilpa Mehta
- David B. Kriser Dental Center, Department of Molecular PathobiologyNew York University College of Dentistry New YorkNew YorkNYUSA
| | - Omer Murik
- Medical Genetics Institute, Shaare Zedek Medical CenterJerusalemIsrael
| | - Geona Altarescu
- Medical Genetics Institute, Shaare Zedek Medical CenterJerusalemIsrael
| | | | - Emi Shimizu
- Oral Biology DepartmentRutgers School of Dental MedicineNewarkNJUSA
| | | | - Shoshana Yakar
- David B. Kriser Dental Center, Department of Molecular PathobiologyNew York University College of Dentistry New YorkNew YorkNYUSA
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Yousefzadeh N, Jeddi S, Kashfi K, Ghasemi A. Diabetoporosis: Role of nitric oxide. EXCLI JOURNAL 2021; 20:764-780. [PMID: 34121973 PMCID: PMC8192884 DOI: 10.17179/excli2021-3541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 03/31/2021] [Indexed: 11/29/2022]
Abstract
Diabetoporosis, diabetic-related decreased bone quality and quantity, is one of the leading causes of osteoporotic fractures in subjects with type 2 diabetes (T2D). This is associated with lower trabecular and cortical bone quality, lower bone turnover rates, lower rates of bone healing, and abnormal posttranslational modifications of collagen. Decreased nitric oxide (NO) bioavailability has been reported within the bones of T2D patients and can be considered as one of the primary mechanisms by which diabetoporosis is manifested. NO donors increase trabecular and cortical bone quality, increase the rate of bone formation, accelerate the bone healing process, delay osteoporosis, and decrease osteoporotic fractures in T2D patients, suggesting the potential therapeutic implication of NO-based interventions. NO is produced in the osteoblast and osteoclast cells by three isoforms of NO synthase (NOS) enzymes. In this review, the roles of NO in bone remodeling in the normal and diabetic states are discussed. Also, the favorable effects of low physiological levels of NO produced by endothelial NOS (eNOS) versus detrimental effects of high pathological levels of NO produced by inducible NOS (iNOS) in diabetoporosis are summarized. Available data indicates decreased bone NO bioavailability in T2D and decreased expression of eNOS, and increased expression and activity of iNOS. NO donors can be considered novel therapeutic agents in diabetoporosis.
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Affiliation(s)
- Nasibeh Yousefzadeh
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sajad Jeddi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Khosrow Kashfi
- Department of Molecular, Cellular, and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, NY, USA
- PhD Program in Biology, City University of New York Graduate Center, New York,NY, USA
| | - Asghar Ghasemi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Fiani B, Newhouse A, Sarhadi KJ, Arshad M, Soula M, Cathel A. Special Considerations to Improve Clinical Outcomes in Patients with Osteoporosis Undergoing Spine Surgery. Int J Spine Surg 2021; 15:386-401. [PMID: 33900998 PMCID: PMC8059385 DOI: 10.14444/8050] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND Osteoporosis is a condition that is commonly encountered, with increasing diagnosis by the medical community with the aging population. Osteoporosis leaves patients susceptible to fragility fractures in the vertebrae and is also associated with degenerative changes, both of which may require intervention from a spine surgeon. The goal of this review is to concisely outline special nonoperative adjuncts, as well as preoperative, intraoperative, and postoperative considerations of osteoporotic patients undergoing spine intervention. METHODS A literature analysis was completed for this narrative review. A database search of PubMed and Google Scholar was conducted using "osteoporosis" combined with "spine," "spine surgery," and "spinal fusion" without exclusion based on publication date. Articles were screened to exclude duplicate articles and screened for their full text and English language availability. RESULTS The database search yielded recent publications from which the narrative review was completed. CONCLUSIONS Preoperatively, screening is traditionally completed with dual-energy x-ray absorptiometry (DEXA). Pharmacological therapy modalities currently include teriparatide, raloxifene, denosumab, bisphosphonates, and calcitonin. In order to prevent operative complications associated with osteoporosis, surgeons have found success in increasing the diameter and the length of pedicle screws, limiting pedicle tapping, achieving bicortical or even tricortical purchase, augmenting with polymethyl methacrylate, using iliosacral stabilization, preventing positive sagittal balance, and using adequate fusion products when necessary. Postoperatively, it is important to implant a care plan that includes adequate pain control and necessary care, and to understand risks associated with falls may increase risk of postoperative fragility fractures as well as instrumentation displacement. At this time there are no recommendations in regard to bracing in the postoperative setting. CLINICAL RELEVANCE This review article outlines the most current evidence-based medicine with regard to considerations in spine surgery of the osteoporotic patient, and aims to bring about new questions to be investigated in that paradigm.
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Affiliation(s)
- Brian Fiani
- Department of Neurosurgery, Desert Regional Medical Center, Palm Springs, California
| | - Alexander Newhouse
- Department of Orthopedic Surgery, Rush University Medical Center, Chicago, Illinois
| | | | - Mohammad Arshad
- Department of Neurosurgery, Desert Regional Medical Center, Palm Springs, California
| | - Marisol Soula
- New York University School of Medicine, New York University, New York, New York
| | - Alessandra Cathel
- Department of Neurosurgery, Desert Regional Medical Center, Palm Springs, California
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Wu LC, Chen HJ, Lin W, Kao HH, Huang PF. Using a simple preliminary screening tool to explore related factors of osteoporosis in the elderly of southern Taiwan. Medicine (Baltimore) 2021; 100:e24950. [PMID: 33655960 PMCID: PMC7939172 DOI: 10.1097/md.0000000000024950] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 02/05/2021] [Indexed: 01/04/2023] Open
Abstract
The aims of this study were to use a simple screening tool to explore related factors with osteoporosis in the elderly in the community of southern Taiwan.This was an observational cross-sectional study using Osteoporosis Self-Assessment Tool for Asia (OSTA), Osteoporosis Self-Assessment Tool for Taiwanese (OSTAi), and the basic demographic information to identify osteoporosis in the participants. This study collected data from 200 participants aged 65 and above and living in southern Taiwan.The prevalence of osteoporosis among elders in the community was 30.5% (OSTA) and 58.0% (OSTAi), respectively. The prevalence of osteoporosis determined by OSTA and OSTAi in female (33.1% and 63.1%, respectively.) was higher than in male (25.7% and 48.6%, respectively.). Risk factors such as gender, age, and body mass index (BMI) were significantly associated with osteoporosis (P < .001). Using OSTA and OSTAi to assess the risk for osteoporosis, for every 1 year of age increase, the odds ratio (OR) value of osteoporosis increased by 1.84 and 1.50 times, respectively (P < .001); for every 1 kg/m2 increase in BMI, the OR of osteoporosis decreases by 0.36 and 0.44 times, respectively. The results of this study can be used a simple tool of OSTA and OSTAi self-examination to screen potential high-risk groups for osteoporosis in the community.OSTA and OSTAi can screen for possible high-risk groups early and without invasive examinations and self-examination tools in a hospital. Low BMI poses higher risks of osteoporosis for the elderly, so increasing functional ability, improving muscle strength, maintaining exercise habits and keeping proper weight could prevent osteoporosis in the seniors.
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Affiliation(s)
- Li-Chu Wu
- Department of Nursing, Kaohsiung Veterans General Hospital, No. 386, Ta-Chung 1st Road
- School of Shu-Zen Junior College Medicine and Management, No.452, Huanqiu Rd. Luzhu Dist
| | - Hong-Jhe Chen
- Department of Family Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, No. 386, Ta-Chung 1st Road, Kaohsiung
| | - Wender Lin
- Department of Health Care Administration, Chang Jung Christian University, No.1 Changda Rd., Gueren Dist., Tainan 711, Taiwan
| | - Hsueh-Hui Kao
- School of Shu-Zen Junior College Medicine and Management, No.452, Huanqiu Rd. Luzhu Dist
| | - Pin-Fang Huang
- Department of Nursing, Kaohsiung Veterans General Hospital, No. 386, Ta-Chung 1st Road
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Peng S, Shi S, Tao G, Li Y, Xiao D, Wang L, He Q, Cai X, Xiao J. JKAMP inhibits the osteogenic capacity of adipose-derived stem cells in diabetic osteoporosis by modulating the Wnt signaling pathway through intragenic DNA methylation. Stem Cell Res Ther 2021; 12:120. [PMID: 33579371 PMCID: PMC7881648 DOI: 10.1186/s13287-021-02163-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 01/12/2021] [Indexed: 02/08/2023] Open
Abstract
Background Diabetic osteoporosis (DOP) is a systemic metabolic bone disease caused by diabetes mellitus (DM). Adipose-derived stem cells (ASCs) play an important role in bone regeneration. Our previous study confirmed that ASCs from DOP mice (DOP-ASCs) have a lower osteogenesis potential compared with control ASCs (CON-ASCs). However, the cause of this poor osteogenesis has not been elucidated. Therefore, this study investigated the underlying mechanism of the decline in the osteogenic potential of DOP-ASCs from the perspective of epigenetics and explored methods to enhance their osteogenic capacity. Methods The expression level of JNK1-associated membrane protein (JKAMP) and degree of DNA methylation in CON-ASCs and DOP-ASCs were measured by mRNA expression profiling and MeDIP sequencing, respectively. JKAMP small interfering RNA (siRNA) and a Jkamp overexpression plasmid were used to assess the role of JKAMP in osteogenic differentiation of CON-ASCs and DOP-ASCs. Immunofluorescence, qPCR, and western blotting were used to measure changes in expression of Wnt signaling pathway-related genes and osteogenesis-related molecules after osteogenesis induction. Alizarin red and ALP staining was used to confirm the osteogenic potential of stem cells. Bisulfite-specific PCR (BSP) was used to detect JKAMP methylation degree. Results Expression of JKAMP and osteogenesis-related molecules (RUNX2 and OPN) in DOP-ASCs was decreased significantly in comparison with CON-ASCs. JKAMP silencing inhibited the Wnt signaling pathway and reduced the osteogenic ability of CON-ASCs. Overexpression of JKAMP in DOP-ASCs rescued the impaired osteogenic capacity caused by DOP. Moreover, JKAMP in DOP-ASCs contained intragenic DNA hypermethylated regions related to the downregulation of JKAMP expression. Conclusions Intragenic DNA methylation inhibits the osteogenic ability of DOP-ASCs by suppressing expression of JKAMP and the Wnt signaling pathway. This study shows an epigenetic explanation for the reduced osteogenic ability of DOP-ASCs and provides a potential therapeutic target to prevent and treat osteoporosis.
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Affiliation(s)
- Shuanglin Peng
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatology Hospital of Southwest Medical University, Luzhou, 646000, China.,State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.,National Key Clinical Specialty, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Sirong Shi
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Gang Tao
- Orofacial Reconstruction and Regeneration Laboratory, The Affiliated Stomatology Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Yanjing Li
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Dexuan Xiao
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Lang Wang
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatology Hospital of Southwest Medical University, Luzhou, 646000, China.,State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Qing He
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatology Hospital of Southwest Medical University, Luzhou, 646000, China.,State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Xiaoxiao Cai
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
| | - Jingang Xiao
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatology Hospital of Southwest Medical University, Luzhou, 646000, China. .,National Key Clinical Specialty, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China. .,Orofacial Reconstruction and Regeneration Laboratory, The Affiliated Stomatology Hospital of Southwest Medical University, Luzhou, 646000, China. .,Department of Oral Implantology, The Affiliated Stomatology Hospital of Southwest Medical University, Luzhou, 646000, China.
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Hildebrandt N, Colditz J, Dutra C, Goes P, Salbach-Hirsch J, Thiele S, Hofbauer LC, Rauner M. Role of osteogenic Dickkopf-1 in bone remodeling and bone healing in mice with type I diabetes mellitus. Sci Rep 2021; 11:1920. [PMID: 33479403 PMCID: PMC7820472 DOI: 10.1038/s41598-021-81543-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Accepted: 01/05/2021] [Indexed: 12/11/2022] Open
Abstract
Type 1 diabetes mellitus (T1DM) is associated with low bone mass and a higher risk for fractures. Dickkopf-1 (Dkk1), which inhibits Wnt signaling, osteoblast function, and bone formation, has been found to be increased in the serum of patients with T1DM. Here, we investigated the functional role of Dkk1 in T1DM-induced bone loss in mice. T1DM was induced in 10-week-old male mice with Dkk1-deficiency in late osteoblasts/osteocytes (Dkk1f/f;Dmp1-Cre, cKO) and littermate control mice by 5 subsequent injections of streptozotocin (40 mg/kg). Age-matched, non-diabetic control groups received citrate buffer instead. At week 12, calvarial defects were created in subgroups of each cohort. After a total of 16 weeks, weight, fat, the femoral bone phenotype and the area of the bone defect were analyzed using µCT and dynamic histomorphometry. During the experiment, diabetic WT and cKO mice did not gain body weight compared to control mice. Further they lost their perigonadal and subcutaneous fat pads. Diabetic mice had highly elevated serum glucose levels and impaired glucose tolerance, regardless of their Dkk1 levels. T1DM led to a 36% decrease in trabecular bone volume in Cre− negative control animals, whereas Dkk1 cKO mice only lost 16%. Of note, Dkk1 cKO mice were completely protected from T1DM-induced cortical bone loss. T1DM suppressed the bone formation rate, the number of osteoblasts at trabecular bone, serum levels of P1NP and bone defect healing in both, Dkk1-deficient and sufficient, mice. This may be explained by increased serum sclerostin levels in both genotypes and the strict dependence on bone formation for bone defect healing. In contrast, the number of osteoclasts and TRACP 5b serum levels only increased in diabetic control mice, but not in Dkk1 cKO mice. In summary, Dkk1 derived from osteogenic cells does not influence the development of T1DM but plays a crucial role in T1DM-induced bone loss in male mice by regulating osteoclast numbers.
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Affiliation(s)
- Nick Hildebrandt
- Department of Medicine III and Center for Healthy Aging, Medical Faculty, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany
| | - Juliane Colditz
- Department of Medicine III and Center for Healthy Aging, Medical Faculty, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.,Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, 04103, Leipzig, Germany
| | - Caio Dutra
- Department of Medicine III and Center for Healthy Aging, Medical Faculty, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.,Post-Graduation Program in Morphological Science, Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Paula Goes
- Department of Medicine III and Center for Healthy Aging, Medical Faculty, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.,Department of Pathology and Legal Medicine, School of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Juliane Salbach-Hirsch
- Department of Medicine III and Center for Healthy Aging, Medical Faculty, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany
| | - Sylvia Thiele
- Department of Medicine III and Center for Healthy Aging, Medical Faculty, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany
| | - Lorenz C Hofbauer
- Department of Medicine III and Center for Healthy Aging, Medical Faculty, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany
| | - Martina Rauner
- Department of Medicine III and Center for Healthy Aging, Medical Faculty, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
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50
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Liu D, Bai JJ, Yao JJ, Wang YB, Chen T, Xing Q, Bai R. Association of Insulin Glargine Treatment with Bone Mineral Density in Patients with Type 2 Diabetes Mellitus. Diabetes Metab Syndr Obes 2021; 14:1909-1917. [PMID: 33953588 PMCID: PMC8092849 DOI: 10.2147/dmso.s302627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 04/01/2021] [Indexed: 11/29/2022] Open
Abstract
PURPOSE To assess the association of type 2 diabetes mellitus (T2DM) and insulin glargine treatment with bone mineral density (BMD) in Chinese people. METHODS This retrospective study included 50 subjects with T2DM: 25 received oral glucose-lowering medication (ORL group), and 25 received oral glucose-lowering medication in combination with insulin glargine injection (CGI group). Thirty non-diabetic control subjects were also included. BMD was measured at lumbar vertebrae 1-4 (L1-L4), spine bone mineral density (sBMD) results summary (L2-L4), femoral neck and trochanter by dual-energy x-ray absorptiometry. RESULTS Compared with non-diabetic controls, people with T2DM had significantly lower mean BMD at L2 (1.073±0.120 vs 0.984±0.158), L3 (1.094±0.129 vs 0.991±0.163) and L4 (1.089±0.130 vs 0.982±0.165) (all P<0.05), significantly lower levels of serum calcium (2.02±0.22 vs 2.27±0.17 mmol/L, P<0.05), PTH (24.19±9.71 vs 31.52±8.96 pg/mL, P<0.05), and higher serum phosphate levels (1.43±0.37 vs 1.20±0.15 mmol/L, P<0.05). The CGI group had higher L2, L3 and L4 BMD and sBMD (L2-L4) (P<0.05), higher serum calcium levels (2.19±0.11 vs 1.98±0.20 mmol/L, P<0.05) and lower serum phosphate levels (1.28±0.20 vs 1.58±0.43 mmol/L, P<0.05) versus the ORL group. BMD and serum calcium levels were associated with the application of insulin glargine. CONCLUSION These results suggest that insulin glargine may affect bone metabolism in patients diagnosed with T2DM. The study has implications for the selection of hypoglycemic agents for diabetic patients at risk of osteoporosis.
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Affiliation(s)
- Dan Liu
- Department of Endocrinology, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China
- Correspondence: Dan Liu; Ran Bai Department of Endocrinology, First Affiliated Hospital of Dalian Medical University, Zhongshan Str.222, Dalian, 116011, People’s Republic of China Email ;
| | - Jing-Jie Bai
- Department of Endocrinology, Dalian Children’s Hospital, Dalian, Liaoning, People’s Republic of China
| | - Jun-Jie Yao
- Department of Endocrinology, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China
| | - Yong-Bo Wang
- Department of Endocrinology, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China
| | - Tong Chen
- Department of Endocrinology, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China
| | - Qian Xing
- Department of Endocrinology, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China
| | - Ran Bai
- Department of Endocrinology, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China
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