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1
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Liu X, Zhao Y, Feng Y, Wang S, Luo A, Zhang J. Ovarian Aging: The Silent Catalyst of Age-Related Disorders in Female Body. Aging Dis 2025:AD.2024.1468. [PMID: 39965250 DOI: 10.14336/ad.2024.1468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 01/27/2025] [Indexed: 02/20/2025] Open
Abstract
Age-related diseases have emerged as a global concern as the population ages. Consequently, understanding the underlying causes of aging and exploring potential anti-aging interventions is imperative. In females, the ovaries serve as the principal organs responsible for ovulation and the production of female hormones. The aging ovaries are related to infertility, menopause, and associated menopausal syndromes, with menopause representing the culmination of ovarian aging. Current evidence indicates that ovarian aging may contribute to dysfunction across multiple organ systems, including, but not limited to, cognitive impairment, osteoporosis, and cardiovascular disease. Nevertheless, due to the widespread distribution of sex hormone receptors throughout the body, ovarian aging affects not only these specific organs but also influences a broader spectrum of age-related diseases in women. Despite this, the impact of ovarian aging on overall age-related diseases has been largely neglected. This review provides a thorough summary of the impact of ovarian aging on age-related diseases, encompassing the nervous, circulatory, locomotor, urinary, digestive, respiratory, and endocrine systems. Additionally, we have outlined prospective therapeutic approaches for addressing both ovarian aging and age-related diseases, with the aim of mitigating their impacts and preserving women's fertility, physical health, and psychological well-being.
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Affiliation(s)
- Xingyu Liu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Huazhong University of Science and Technology, Wuhan, 430030, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yuanqu Zhao
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Huazhong University of Science and Technology, Wuhan, 430030, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yanzhi Feng
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Huazhong University of Science and Technology, Wuhan, 430030, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Shixuan Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Huazhong University of Science and Technology, Wuhan, 430030, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Aiyue Luo
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Huazhong University of Science and Technology, Wuhan, 430030, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jinjin Zhang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Huazhong University of Science and Technology, Wuhan, 430030, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Huazhong University of Science and Technology, Wuhan, 430030, China
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Kim J, Bang H, Seong C, Kim ES, Kim SY. Transcription factors and hormone receptors: Sex‑specific targets for cancer therapy (Review). Oncol Lett 2025; 29:93. [PMID: 39691589 PMCID: PMC11650965 DOI: 10.3892/ol.2024.14839] [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: 08/20/2024] [Accepted: 11/15/2024] [Indexed: 12/19/2024] Open
Abstract
Despite advancements in diagnostic and therapeutic technologies, cancer continues to pose a challenge to disease-free longevity in humans. Numerous factors contribute to the onset and progression of cancer, among which sex differences, as an intrinsic biological condition, warrant further attention. The present review summarizes the roles of hormone receptors estrogen receptor α (ERα), estrogen receptor β (ERβ) and androgen receptor (AR) in seven types of cancer: Breast, prostate, ovarian, lung, gastric, colon and liver cancer. Key cancer-related transcription factors known to be activated through interactions with these hormone receptors have also been discussed. To assess the impact of sex hormone receptors on different cancer types, hormone-related transcription factors were analyzed using the SignaLink 3.0 database. Further analysis focused on six key transcription factors: CCCTC-binding factor, forkhead box A1, retinoic acid receptor α, PBX homeobox 1, GATA binding protein 2 and CDK inhibitor 1A. The present review demonstrates that these transcription factors significantly influence hormone receptor activity across various types of cancer, and elucidates the complex interactions between these transcription factors and hormone receptors, offering new insights into their roles in cancer progression. The findings suggest that targeting these common transcription factors could improve the efficacy of hormone therapy and provide a unified approach to treating various types of cancer. Understanding the dual and context-dependent roles of these transcription factors deepens the current understanding of the molecular mechanisms underlying hormone-driven tumor progression and could lead to more effective targeted therapeutic strategies.
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Affiliation(s)
- Juyeon Kim
- Department of Chemistry, College of Science and Technology, Duksung Women's University, Seoul 01369, Republic of Korea
| | - Hyobin Bang
- Department of Chemistry, College of Science and Technology, Duksung Women's University, Seoul 01369, Republic of Korea
| | - Cheyun Seong
- Department of Chemistry, College of Science and Technology, Duksung Women's University, Seoul 01369, Republic of Korea
| | - Eun-Sook Kim
- College of Pharmacy, Duksung Women's University, Seoul 01369, Republic of Korea
| | - Sun Young Kim
- Department of Chemistry, College of Science and Technology, Duksung Women's University, Seoul 01369, Republic of Korea
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Li G, Wang A, Tang W, Fu W, Tian Q, Jian J, Lata M, Hettinghouse A, Ding Y, Wei J, Zhao X, Wang M, Dong Q, Liu C, Xu Y. Progranulin deficiency associates with postmenopausal osteoporosis via increasing ubiquitination of estrogen receptor α. Genes Dis 2025; 12:101221. [PMID: 39559258 PMCID: PMC11570241 DOI: 10.1016/j.gendis.2024.101221] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 12/27/2023] [Accepted: 12/31/2023] [Indexed: 11/20/2024] Open
Abstract
Estrogen deficiency is considered the most important cause of postmenopausal osteoporosis. However, the underlying mechanism is still not completely understood. In this study, progranulin (PGRN) was isolated as a key regulator of bone mineral density in postmenopausal women through high throughput proteomics screening. In addition, PGRN-deficient mice exhibited significantly lower bone mass than their littermates in an ovariectomy-induced osteoporosis model. Furthermore, estrogen-mediated inhibition of osteoclastogenesis and bone resorption as well as its protection against ovariectomy-induced bone loss largely depended on PGRN. Mechanistic studies revealed the existence of a positive feedback regulatory loop between PGRN and estrogen signaling. In addition, loss of PGRN led to the reduction of estrogen receptor α, the important estrogen receptor involved in estrogen regulation of osteoporosis, through enhancing its degradation via K48-linked ubiquitination. These findings not only provide a previously unrecognized interplay between PGRN and estrogen signaling in regulating osteoclastogenesis and osteoporosis but may also present a new therapeutic approach for the prevention and treatment of postmenopausal osteoporosis by targeting PGRN/estrogen receptor α.
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Affiliation(s)
- Guangfei Li
- Department of Orthopedics, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
- Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY 10003, USA
- Osteoporosis Institute of Soochow University, Suzhou, Jiangsu 215004, China
| | - Aifei Wang
- Department of Orthopedics, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
- Osteoporosis Institute of Soochow University, Suzhou, Jiangsu 215004, China
| | - Wei Tang
- Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY 10003, USA
- Department of Pathogenic Biology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China
| | - Wenyu Fu
- Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY 10003, USA
- Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Qingyun Tian
- Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY 10003, USA
| | - Jinlong Jian
- Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY 10003, USA
| | - Michal Lata
- Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY 10003, USA
| | - Aubryanna Hettinghouse
- Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY 10003, USA
| | - Yuanjing Ding
- Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY 10003, USA
- Department of Orthopaedic Surgery, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250013, China
| | - Jianlu Wei
- Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY 10003, USA
- Department of Orthopaedic Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
| | - Xiangli Zhao
- Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY 10003, USA
| | - Mingyong Wang
- Murui Biological Technology Co., Ltd., Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Qirong Dong
- Department of Orthopedics, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Chuanju Liu
- Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY 10003, USA
- Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06510, USA
- Department of Cell Biology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Youjia Xu
- Department of Orthopedics, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
- Osteoporosis Institute of Soochow University, Suzhou, Jiangsu 215004, China
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Jang B, Kim Y, Song J, Kim YW, Lee WY. Identifying Herbal Candidates and Active Ingredients Against Postmenopausal Osteoporosis Using Biased Random Walk on a Multiscale Network. Int J Mol Sci 2024; 25:12322. [PMID: 39596387 PMCID: PMC11594441 DOI: 10.3390/ijms252212322] [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: 11/01/2024] [Revised: 11/13/2024] [Accepted: 11/14/2024] [Indexed: 11/28/2024] Open
Abstract
Postmenopausal osteoporosis is a major global health concern, particularly affecting aging women, and necessitates innovative treatment options. Herbal medicine, with its multi-compound, multi-target characteristics, offers a promising approach for complex diseases. In this study, we applied multiscale network and random walk-based analyses to identify candidate herbs and their active ingredients for postmenopausal osteoporosis, focusing on their underlying mechanisms. A dataset of medicinal herbs, their active ingredients, and protein targets was compiled, and diffusion profiles were calculated to assess the propagation effects. Through correlation analysis, we prioritized herbs based on their relevance to osteoporosis, identifying the top candidates like Benincasae Semen, Glehniae Radix, Corydalis Tuber, and Houttuyniae Herba. Gene Set Enrichment Analysis (GSEA) revealed that the 49 core protein targets of these herbs were significantly associated with pathways related to inflammation, osteoclast differentiation, and estrogen metabolism. Notably, compounds such as falcarindiol from Glehniae Radix and tetrahydrocoptisine from Corydalis Tuber-previously unstudied for osteoporosis-were predicted to interact with inflammation-related proteins, including IL6, IL1B, and TNF, affecting key biological processes like apoptosis and cell proliferation. This study advances the understanding of herbal therapies for osteoporosis and offers a framework for discovering novel therapeutic agents.
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Affiliation(s)
- Boyun Jang
- IntegroMediLab Co., Ltd., Seoul 04626, Republic of Korea
| | - Youngsoo Kim
- IntegroMediLab Co., Ltd., Seoul 04626, Republic of Korea
| | - Jungbin Song
- Department of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Young-Woo Kim
- School of Korean Medicine, Dongguk University, Gyeongju 38066, Republic of Korea
| | - Won-Yung Lee
- School of Korean Medicine, Wonkwang University, Iksan 54538, Republic of Korea
- Research Center of Traditional Korean Medicine, Wonkwang University, Iksan 54538, Republic of Korea
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Labelle-Dumais C, Mazur C, Kaya S, Obata Y, Lee B, Acevedo C, Alliston T, Gould DB. Skeletal pathology in mouse models of Gould syndrome is partially alleviated by genetically reducing TGFβ signaling. Matrix Biol 2024; 133:1-13. [PMID: 39097038 DOI: 10.1016/j.matbio.2024.07.005] [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: 05/25/2024] [Revised: 07/30/2024] [Accepted: 07/31/2024] [Indexed: 08/05/2024]
Abstract
Skeletal defects are hallmark features of many extracellular matrix (ECM) and collagen-related disorders. However, a biological function in bone has never been defined for the highly evolutionarily conserved type IV collagen. Collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) form α1α1α2 (IV) heterotrimers that represent a fundamental basement membrane constituent present in every organ of the body, including the skeleton. COL4A1 and COL4A2 mutations cause Gould syndrome, a variable and clinically heterogenous multisystem disorder generally characterized by the presence of cerebrovascular disease with ocular, renal, and muscular manifestations. We have previously identified elevated TGFβ signaling as a pathological insult resulting from Col4a1 mutations and demonstrated that reducing TGFβ signaling ameliorate ocular and cerebrovascular phenotypes in Col4a1 mutant mouse models of Gould syndrome. In this study, we describe the first characterization of skeletal defects in Col4a1 mutant mice that include a developmental delay in osteogenesis and structural, biomechanical and vascular alterations of mature bones. Using distinct mouse models, we show that allelic heterogeneity influences the presentation of skeletal pathology resulting from Col4a1 mutations. Importantly, we found that TGFβ target gene expression is elevated in developing bones from Col4a1 mutant mice and show that genetically reducing TGFβ signaling partially ameliorates skeletal manifestations. Collectively, these findings identify a novel and unsuspected role for type IV collagen in bone biology, expand the spectrum of manifestations associated with Gould syndrome to include skeletal abnormalities, and implicate elevated TGFβ signaling in skeletal pathogenesis in Col4a1 mutant mice.
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Affiliation(s)
- Cassandre Labelle-Dumais
- Departments of Ophthalmology, University of California San Francisco, San Francisco, CA 94143, USA
| | - Courtney Mazur
- Department of Orthopaedic Surgery, University of California San Francisco, San Francisco, CA, 94143, USA; UC Berkeley/UCSF Graduate Program in Bioengineering, San Francisco, CA 94143, USA
| | - Serra Kaya
- Department of Orthopaedic Surgery, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Yoshihiro Obata
- Department of Mechanical and Aerospace Engineering, University of California San Diego, San Diego, CA 92093, USA
| | - Bryson Lee
- Departments of Ophthalmology, University of California San Francisco, San Francisco, CA 94143, USA
| | - Claire Acevedo
- Department of Orthopaedic Surgery, University of California San Francisco, San Francisco, CA, 94143, USA; Materials Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Department of Mechanical and Aerospace Engineering, University of California San Diego, San Diego, CA 92093, USA
| | - Tamara Alliston
- Department of Orthopaedic Surgery, University of California San Francisco, San Francisco, CA, 94143, USA; UC Berkeley/UCSF Graduate Program in Bioengineering, San Francisco, CA 94143, USA
| | - Douglas B Gould
- Departments of Ophthalmology, University of California San Francisco, San Francisco, CA 94143, USA; Department of Anatomy, Institute for Human Genetics, Bakar Aging Research Institute, and Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94143, USA.
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6
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Ruivo AK, Calsa B, Cancellara MG, Lima JPN, da Silva KR, Esquisatto MAM, Santamaria-Jr M. Effect of estrogen depression on alveolar bone microarchitecture and periodontal ligament cells during orthodontic movement. Eur J Oral Sci 2024; 132:e13014. [PMID: 39160699 DOI: 10.1111/eos.13014] [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: 05/08/2024] [Revised: 07/30/2024] [Accepted: 07/31/2024] [Indexed: 08/21/2024]
Abstract
This study aimed to evaluate the effects of the estrogen depression during orthodontic tooth movement on alveolar bone microarchitecture and periodontal ligament. Female Wistar rats were divided into two groups, one consisting of non-ovariectomized animals subjected to orthodontic tooth movement, and one comprising ovariectomized animals subjected to orthodontic tooth movement. Micro-CT assessment of bone volume to total volume (BV/TV), total porosity, trabecular thickness (Tb.Th), trabecular number (Tb.N), and trabecular separation (Tb.Sp) in the alveolar bone of the orthodontically moved tooth was performed. Histomorphometric analyses were made in the periodontal ligament, and immunoexpression of RANK, RANKL, OPG, and TUNEL were quantified. Orthodontic tooth movement in the group of ovariectomized rats was faster than in non-ovariectomized animals. The alveolar bone area showed lower values of BV/TV and trabecular thickness, and higher bone porosity and trabeculae numbers in the ovariectomized rats. Histological analyses in the ovariectomized group revealed an increase in collagen fibers in the periodontal ligament. The apoptotic cell counts in the periodontal ligament were higher in the group of ovariectomized rats than in the sham-operated rats. Ovariectomy resulted in an increase in tooth movement and alteration of the alveolar bone microstructure in the first 7 day of orthodontic tooth movement, and in the presence of apoptotic cells in the periodontal ligament.
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Affiliation(s)
- Andréa Karina Ruivo
- Graduate Program in Odontology, University Center of the Hermínio Ometto Foundation - FHO, Araras, SP, Brazil
| | - Bruno Calsa
- Department of Internal Medicine, Faculty of Medical Sciences at State University of Campinas - UNICAMP, Campinas, SP, Brazil
| | - Matheus Gomez Cancellara
- Department of Social and Pediatric Dentistry, Institute of Science and Technology - College of Dentistry, São Paulo State University - Unesp, São José dos Campos, SP, Brazil
| | - João Paulo Nascimento Lima
- Graduate Program in Odontology, University Center of the Hermínio Ometto Foundation - FHO, Araras, SP, Brazil
| | - Karla Rovaris da Silva
- Department of Pathology and Dental Clinic, Federal University of Piaui, Teresina, PI, Brazil
| | | | - Milton Santamaria-Jr
- Graduate Program in Odontology, University Center of the Hermínio Ometto Foundation - FHO, Araras, SP, Brazil
- Department of Social and Pediatric Dentistry, Institute of Science and Technology - College of Dentistry, São Paulo State University - Unesp, São José dos Campos, SP, Brazil
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7
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Qin L, Liu Q, Zhang T, Tang X, Mo X, Liang Y, Wang X, Cao J, Huang C, Lu Y, Zhang Z, Qin J, Cai J. Association Between Combined Polymetallic Exposure and Osteoporosis. Biol Trace Elem Res 2024; 202:3945-3958. [PMID: 38109003 DOI: 10.1007/s12011-023-04002-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 12/05/2023] [Indexed: 12/19/2023]
Abstract
Combined polymetallic exposure may be an influential factor in osteoporosis. This study aimed to explore the association between polymetallic combined exposure and osteoporosis. A total of 2115 participants were included. Plasma concentrations of 22 metals were determined by inductively coupled plasma mass spectrometry. Osteoporosis was defined as a T ≤ - 2.5. The least absolute shrinkage and selection operator (LASSO) regression, binary logistics regression, and Bayesian kernel machine regression (BKMR) model were used to explore the association between plasma metals and osteoporosis. LASSO regression showed that 10 metals were associated with osteoporosis in the total population (magnesium, calcium, manganese, nickel, cobalt, arsenic, selenium, rubidium, cadmium, aluminum) and women (magnesium, calcium, molybdenum, nickel, cobalt, arsenic, selenium, rubidium, cadmium, aluminum), and four metals associated with men (magnesium, cobalt, aluminum, iron). Logistics regression showed that in total population, magnesium (ORQ3 = 0.653, 95% CI = 0.446-0.954) was negatively correlated with osteoporosis, while aluminum (ORQ2 = 1.569, 95% CI = 1.095-2.248, ORQ4 = 1.616, 95% CI = 1.109-2.354) and cadmium (ORQ4 = 1.989, 95% CI = 1.379-2.870) were positively correlated; in women, magnesium (ORQ3 = 0.579, 95% CI = 0.379-0.883) was negatively correlated with osteoporosis, while aluminum (ORQ2 = 1.563, 95% CI = 1.051-2.326, ORQ4 = 1.543, 95% CI = 1.024-2.326) and cadmium (ORQ3 = 1.482, 95% CI = 1.003-2.191, ORQ4 = 1.740, 95% CI = 1.167-2.596) were positively correlated. BKMR model showed that combined polymetallic exposure had an overall positive effect on osteoporosis, magnesium was negatively associated with osteoporosis, and cadmium, selenium, and aluminum were positively associated with osteoporosis. Metal mixtures in plasma were associated with osteoporosis risk. Magnesium may reduce the risk of osteoporosis, while cadmium, selenium, and aluminum may increase the risk of osteoporosis. Future studies needed to explore correlations and mechanisms.
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Affiliation(s)
- Lidong Qin
- Department of Environmental and Occupational Health, School of Public Health, Guangxi Medical University, Shuangyong Road 22, Nanning, 530021, Guangxi, China
| | - Qiumei Liu
- Department of Environmental and Occupational Health, School of Public Health, Guangxi Medical University, Shuangyong Road 22, Nanning, 530021, Guangxi, China
| | - Tiantian Zhang
- Department of Environmental and Occupational Health, School of Public Health, Guangxi Medical University, Shuangyong Road 22, Nanning, 530021, Guangxi, China
| | - Xu Tang
- Department of Environmental and Occupational Health, School of Public Health, Guangxi Medical University, Shuangyong Road 22, Nanning, 530021, Guangxi, China
| | - Xiaoting Mo
- Department of Environmental and Occupational Health, School of Public Health, Guangxi Medical University, Shuangyong Road 22, Nanning, 530021, Guangxi, China
| | - Yujian Liang
- Department of Environmental and Occupational Health, School of Public Health, Guangxi Medical University, Shuangyong Road 22, Nanning, 530021, Guangxi, China
| | - Xuexiu Wang
- Department of Environmental and Occupational Health, School of Public Health, Guangxi Medical University, Shuangyong Road 22, Nanning, 530021, Guangxi, China
| | - Jiejing Cao
- Department of Environmental and Occupational Health, School of Public Health, Guangxi Medical University, Shuangyong Road 22, Nanning, 530021, Guangxi, China
| | - Chuwu Huang
- Department of Environmental and Occupational Health, School of Public Health, Guangxi Medical University, Shuangyong Road 22, Nanning, 530021, Guangxi, China
| | - Yufu Lu
- Department of Environmental and Occupational Health, School of Public Health, Guangxi Medical University, Shuangyong Road 22, Nanning, 530021, Guangxi, China
| | - Zhiyong Zhang
- Department of Environmental and Occupational Health, School of Public Health, Guangxi Medical University, Shuangyong Road 22, Nanning, 530021, Guangxi, China
- Department of Environmental Health and Occupational Medicine, School of Public Health, Guilin Medical University, Guilin, China
- Guangxi Health Commission Key Laboratory of Entire Lifecycle Health and Care, Guilin Medical University, Guilin, China
| | - Jian Qin
- Department of Environmental and Occupational Health, School of Public Health, Guangxi Medical University, Shuangyong Road 22, Nanning, 530021, Guangxi, China.
- Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, China.
- Guangxi Key Laboratory of Environment and Health Research, Guangxi Medical University, Nanning, China.
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Guangxi Medical University, Nanning, China.
| | - Jiansheng Cai
- Department of Environmental and Occupational Health, School of Public Health, Guangxi Medical University, Shuangyong Road 22, Nanning, 530021, Guangxi, China.
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Huan Cheng North 2Nd Road 109, Guilin, 541004, Guangxi, China.
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8
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Chen C, Cao Z, Lei H, Zhang C, Wu M, Huang S, Li X, Xie D, Liu M, Zhang L, Chen G. Microbial Tryptophan Metabolites Ameliorate Ovariectomy-Induced Bone Loss by Repairing Intestinal AhR-Mediated Gut-Bone Signaling Pathway. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2404545. [PMID: 39041942 PMCID: PMC11423200 DOI: 10.1002/advs.202404545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 06/03/2024] [Indexed: 07/24/2024]
Abstract
Microbial tryptophan (Trp) metabolites acting as aryl hydrocarbon receptor (AhR) ligands are shown to effectively improve metabolic diseases via regulating microbial community. However, the underlying mechanisms by which Trp metabolites ameliorate bone loss via gut-bone crosstalk are largely unknown. In this study, supplementation with Trp metabolites, indole acetic acid (IAA), and indole-3-propionic acid (IPA), markedly ameliorate bone loss by repairing intestinal barrier integrity in ovariectomy (OVX)-induced postmenopausal osteoporosis mice in an AhR-dependent manner. Mechanistically, intestinal AhR activation by Trp metabolites, especially IAA, effectively repairs intestinal barrier function by stimulating Wnt/β-catenin signaling pathway. Consequently, enhanced M2 macrophage by supplementation with IAA and IPA secrete large amount of IL-10 that expands from intestinal lamina propria to bone marrow, thereby simultaneously promoting osteoblastogenesis and inhibiting osteoclastogenesis in vivo and in vitro. Interestingly, supplementation with Trp metabolites exhibit negligible ameliorative effects on both gut homeostasis and bone loss of OVX mice with intestinal AhR knockout (VillinCreAhrfl/fl). These findings suggest that microbial Trp metabolites may be potential therapeutic candidates against osteoporosis via regulating AhR-mediated gut-bone axis.
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Affiliation(s)
- Chuan Chen
- State Key Laboratory of Magnetic Resonance and ImagingNational Centre for Magnetic Resonance in WuhanInnovation Academy of Precision Measurement Science and TechnologyCASWuhan430071China
- University of Chinese Academy of SciencesBeijing100049China
| | - Zheng Cao
- State Key Laboratory of Magnetic Resonance and ImagingNational Centre for Magnetic Resonance in WuhanInnovation Academy of Precision Measurement Science and TechnologyCASWuhan430071China
- University of Chinese Academy of SciencesBeijing100049China
| | - Hehua Lei
- State Key Laboratory of Magnetic Resonance and ImagingNational Centre for Magnetic Resonance in WuhanInnovation Academy of Precision Measurement Science and TechnologyCASWuhan430071China
- University of Chinese Academy of SciencesBeijing100049China
| | - Cui Zhang
- State Key Laboratory of Magnetic Resonance and ImagingNational Centre for Magnetic Resonance in WuhanInnovation Academy of Precision Measurement Science and TechnologyCASWuhan430071China
- University of Chinese Academy of SciencesBeijing100049China
| | - Mengjing Wu
- State Key Laboratory of Magnetic Resonance and ImagingNational Centre for Magnetic Resonance in WuhanInnovation Academy of Precision Measurement Science and TechnologyCASWuhan430071China
- University of Chinese Academy of SciencesBeijing100049China
| | - Shaohua Huang
- Institute of Drug Discovery and TechnologyNingbo UniversityNingbo315211China
| | - Xinzhi Li
- School of Pharmacy and State Key Laboratory of Quality Research in Chinese MedicineMacau University of Science and TechnologyMacau999078China
| | - Denghui Xie
- Department of Joint SurgeryCenter for Orthopaedic SurgeryThe Third Affiliated Hospital of Southern Medical UniversityGuangzhou510515China
| | - Maili Liu
- State Key Laboratory of Magnetic Resonance and ImagingNational Centre for Magnetic Resonance in WuhanInnovation Academy of Precision Measurement Science and TechnologyCASWuhan430071China
- University of Chinese Academy of SciencesBeijing100049China
| | - Limin Zhang
- State Key Laboratory of Magnetic Resonance and ImagingNational Centre for Magnetic Resonance in WuhanInnovation Academy of Precision Measurement Science and TechnologyCASWuhan430071China
- University of Chinese Academy of SciencesBeijing100049China
| | - Gang Chen
- Department of GeriatricsHubei Provincial Hospital of Traditional Chinese Medicine (Affiliated Hospital of Hubei University of Chinese Medicine)Wuhan430060China
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9
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Gao H, Peng X, Li N, Gou L, Xu T, Wang Y, Qin J, Liang H, Ma P, Li S, Wu J, Qin X, Xue B. Emerging role of liver-bone axis in osteoporosis. J Orthop Translat 2024; 48:217-231. [PMID: 39290849 PMCID: PMC11407911 DOI: 10.1016/j.jot.2024.07.008] [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: 03/06/2024] [Revised: 06/19/2024] [Accepted: 07/16/2024] [Indexed: 09/19/2024] Open
Abstract
Background Increasing attention to liver-bone crosstalk has spurred interest in targeted interventions for various forms of osteoporosis. Liver injury induced by different liver diseases can cause an imbalance in bone metabolism, indicating a novel regulatory paradigm between the liver and bone. However, the role of the liver-bone axis in both primary and secondary osteoporosis remains inadequately elucidated. Therefore, exploring the exact regulatory mechanisms of the liver-bone axis may offer innovative clinical approaches for treating diseases associated with the liver and bone. Methods Here, we summarize the latest research on the liver-bone axis by searching the PubMed and Web of Science databases and discuss the possible mechanism of the liver-bone axis in different types of osteoporosis. The literature directly reporting the regulatory role of the liver-bone axis in different types of osteoporosis from the PubMed and Web of Science databases has been included in the discussion of this review (including but not limited to the definition of the liver-bone axis, clinical studies, and basic research). In addition, articles discussing changes in bone metabolism caused by different etiologies of liver injury have also been included in the discussion of this review (including but not limited to clinical studies and basic research). Results Several endocrine factors (IGF-1, FGF21, hepcidin, vitamin D, osteocalcin, OPN, LCAT, Fetuin-A, PGs, BMP2/9, IL-1/6/17, and TNF-α) and key genes (SIRT2, ABCB4, ALDH2, TFR2, SPTBN1, ZNF687 and SREBP2) might be involved in the regulation of the liver-bone axis. In addition to the classic metabolic pathways involved in inflammation and oxidative stress, iron metabolism, cholesterol metabolism, lipid metabolism and immunometabolism mediated by the liver-bone axis require more research to elucidate the regulatory mechanisms involved in osteoporosis. Conclusion During primary and secondary osteoporosis, the liver-bone axis is responsible for liver and bone homeostasis via several hepatokines and osteokines as well as biochemical signaling. Combining multiomics technology and data mining technology could further advance our understanding of the liver-bone axis, providing new clinical strategies for managing liver and bone-related diseases.The translational potential of this article is as follows: Abnormal metabolism in the liver could seriously affect the metabolic imbalance of bone. This review summarizes the indispensable role of several endocrine factors and biochemical signaling pathways involved in the liver-bone axis and emphasizes the important role of liver metabolic homeostasis in the pathogenesis of osteoporosis, which provides novel potential directions for the prevention, diagnosis, and treatment of liver and bone-related diseases.
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Affiliation(s)
- Hongliang Gao
- Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China
- Jiangsu Key Laboratory of Early Development and Chronic Disease Prevention in Children,Nanjing, Jiangsu,PR China
- Core Laboratory, Department of Clinical Laboratory, Sir Run Run Hospital, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, PR China
- Department of pathophysiology, Wannan Medical College, Wuhu, Anhui, PR China
| | - Xing Peng
- Core Laboratory, Department of Clinical Laboratory, Sir Run Run Hospital, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Ning Li
- Core Laboratory, Department of Clinical Laboratory, Sir Run Run Hospital, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Liming Gou
- Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China
- Jiangsu Key Laboratory of Early Development and Chronic Disease Prevention in Children,Nanjing, Jiangsu,PR China
| | - Tao Xu
- Core Laboratory, Department of Clinical Laboratory, Sir Run Run Hospital, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Yuqi Wang
- Core Laboratory, Department of Clinical Laboratory, Sir Run Run Hospital, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Jian Qin
- Department of Orthoprdics, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu , PR China
| | - Hui Liang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Peiqi Ma
- Medical Imaging Center, Fuyang People's Hospital, Fuyang, Anhui, PR China
| | - Shu Li
- Department of pathophysiology, Wannan Medical College, Wuhu, Anhui, PR China
| | - Jing Wu
- Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China
- Jiangsu Key Laboratory of Early Development and Chronic Disease Prevention in Children,Nanjing, Jiangsu,PR China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Xihu Qin
- Department of General Surgery, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, PR China
| | - Bin Xue
- Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China
- Jiangsu Key Laboratory of Early Development and Chronic Disease Prevention in Children,Nanjing, Jiangsu,PR China
- Core Laboratory, Department of Clinical Laboratory, Sir Run Run Hospital, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, PR China
- Department of General Surgery, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, PR China
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10
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Hu X, Wang Z, Wang W, Cui P, Kong C, Chen X, Lu S. Irisin as an agent for protecting against osteoporosis: A review of the current mechanisms and pathways. J Adv Res 2024; 62:175-186. [PMID: 37669714 PMCID: PMC11331170 DOI: 10.1016/j.jare.2023.09.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/24/2023] [Accepted: 09/01/2023] [Indexed: 09/07/2023] Open
Abstract
BACKGROUND Osteoporosis is recognized as a skeletal disorder characterized by diminished bone tissue quality and density. Regular physical exercise is widely acknowledged to preserve and enhance bone health, but the detailed molecular mechanisms involved remain unclear. Irisin, a factor derived from muscle during exercise, influences bone and muscle. Since its discovery in 2012, irisin has been found to promote bone growth and reduce bone resorption, establishing a tangible link between muscle exertion and bone health. Consequently, the mechanism by which irisin prevents osteoporosis have attracted significant scientific interest. AIM OF THE REVIEW This study aims to elucidate the multifaceted relationship between exercise, irisin, and bone health. Focusing on irisin, a muscle-derived factor released during exercise, we seek to understand its role in promoting bone growth and inhibiting resorption. Through a review of current research article on irisin in osteoporosis, Our review provides a deep dive into existing research on influence of irisin in osteoporosis, exploring its interaction with pivotal signaling pathways and its impact on various cell death mechanisms and inflammation. We aim to uncover the molecular underpinnings of how irisin, secreted during exercise, can serve as a therapeutic strategy for osteoporosis. KEY SCIENTIFIC CONCEPTS OF THE REVIEW Irisin, secreted during exercise, plays a vital role in bridging muscle function to bone health. It not only promotes bone growth but also inhibits bone resorption. Specifically, Irisin fosters osteoblast proliferation, differentiation, and mineralization predominantly through the ERK, p38, and AMPK signaling pathways. Concurrently, it regulates osteoclast differentiation and maturation via the JNK, Wnt/β-catenin and RANKL/RANK/OPG signaling pathways. This review further delves into the profound significance of irisin in osteoporosis and its involvement in diverse cellular death mechanisms, including apoptosis, autophagy, ferroptosis, and pyroptosis.
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Affiliation(s)
- Xinli Hu
- Department of Orthopedics, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Xicheng District, Beijing 100053, China; National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Zheng Wang
- Department of Orthopedics, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Xicheng District, Beijing 100053, China; National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Wei Wang
- Department of Orthopedics, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Xicheng District, Beijing 100053, China; National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Peng Cui
- Department of Orthopedics, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Xicheng District, Beijing 100053, China; National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Chao Kong
- Department of Orthopedics, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Xicheng District, Beijing 100053, China; National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
| | - Xiaolong Chen
- Department of Orthopedics, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Xicheng District, Beijing 100053, China; National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
| | - Shibao Lu
- Department of Orthopedics, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Xicheng District, Beijing 100053, China; National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
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11
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Li Z, Cheng W, Gao K, Liang S, Ke L, Wang M, Fan J, Li D, Zhang P, Xu Z, Li N. Pyroptosis: A spoiler of peaceful coexistence between cells in degenerative bone and joint diseases. J Adv Res 2024:S2090-1232(24)00247-9. [PMID: 38876191 DOI: 10.1016/j.jare.2024.06.010] [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: 02/17/2024] [Revised: 05/23/2024] [Accepted: 06/07/2024] [Indexed: 06/16/2024] Open
Abstract
BACKGROUND As people age, degenerative bone and joint diseases (DBJDs) become more prevalent. When middle-aged and elderly people are diagnosed with one or more disorders such as osteoporosis (OP), osteoarthritis (OA), and intervertebral disc degeneration (IVDD), it often signals the onset of prolonged pain and reduced functionality. Chronic inflammation has been identified as the underlying cause of various degenerative diseases, including DBJDs. Recently, excessive activation of pyroptosis, a form of programed cell death (PCD) mediated by inflammasomes, has emerged as a primary driver of harmful chronic inflammation. Consequently, pyroptosis has become a potential target for preventing and treating DBJDs. AIM OF REVIEW This review explored the physiological and pathological roles of the pyroptosis pathway in bone and joint development and its relation to DBJDs. Meanwhile, it elaborated the molecular mechanisms of pyroptosis within individual cell types in the bone marrow and joints, as well as the interplay among different cell types in the context of DBJDs. Furthermore, this review presented the latest compelling evidence supporting the idea of regulating the pyroptosis pathway for DBJDs treatment, and discussed the potential, limitations, and challenges of various therapeutic strategies involving pyroptosis regulation. KEY SCIENTIFIC CONCEPTS OF REVIEW In summary, an interesting identity for the unregulated pyroptosis pathway in the context of DBJDs was proposed in this review, which was undertaken as a spoiler of peaceful coexistence between cells in a degenerative environment. Over the extended course of DBJDs, pyroptosis pathway perpetuated its activity through crosstalk among pyroptosis cascades in different cell types, thus exacerbating the inflammatory environment throughout the entire bone marrow and joint degeneration environment. Correspondingly, pyroptosis regulation therapy emerged as a promising option for clinical treatment of DBJDs.
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Affiliation(s)
- Zhichao Li
- First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250014, China; Department of Orthopedics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250014, China; Center for Translational Medicine Research and Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Wenxiang Cheng
- Center for Translational Medicine Research and Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Kuanhui Gao
- First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250014, China
| | - Songlin Liang
- First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250014, China; Center for Translational Medicine Research and Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Liqing Ke
- Center for Translational Medicine Research and Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Mengjie Wang
- First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250014, China
| | - Jilin Fan
- First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250014, China
| | - Dandan Li
- College of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050011, China
| | - Peng Zhang
- Center for Translational Medicine Research and Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Faculty of Biomedical Engineering, Shenzhen University of Advanced Technology, Shenzhen 518000, China; Key Laboratory of Biomedical Imaging Science and System, Chinese Academy of Sciences, Shenzhen, 518000 China; Shandong Zhongke Advanced Technology Co., Ltd., Jinan, 250300 China.
| | - Zhanwang Xu
- First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250014, China; Department of Orthopedics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250014, China.
| | - Nianhu Li
- First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250014, China; Department of Orthopedics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250014, China.
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12
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Gandhi N, Omer S, Harrison RE. In Vitro Cell Culture Model for Osteoclast Activation during Estrogen Withdrawal. Int J Mol Sci 2024; 25:6134. [PMID: 38892322 PMCID: PMC11173070 DOI: 10.3390/ijms25116134] [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: 04/22/2024] [Revised: 05/22/2024] [Accepted: 05/24/2024] [Indexed: 06/21/2024] Open
Abstract
Estrogen (17β-estradiol) deficiency post-menopause alters bone homeostasis whereby bone resorption by osteoclasts exceeds bone formation by osteoblasts, leading to osteoporosis in females. We established an in vitro model to examine the consequences of estrogen withdrawal (E2-WD) on osteoclasts derived from the mouse macrophage RAW 264.7 cell line and utilized it to investigate the mechanism behind the enhanced osteoclast activity post-menopause. We found that a greater population of osteoclasts that underwent E2-WD contained a podosome belt necessary for osteoclasts to adhere and resorb bone and possessed elevated resorptive activity compared to osteoclasts exposed to estrogen (E2) continuously. Our results show that compared to osteoclasts that received E2 continuously, those that underwent E2-WD had a faster rate of microtubule (MT) growth, reduced RhoA activation, and shorter podosome lifespan. Thus, altered podosome and MT dynamics induced by the withdrawal of estrogen supports podosome belt assembly/stability in osteoclasts, which may explain their enhanced bone resorption activity.
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Affiliation(s)
- Nisha Gandhi
- Department of Cell & Systems Biology, University of Toronto Scarborough, Toronto, ON M1C 1A4, Canada;
| | - Safia Omer
- Department of Biological Sciences, University of Toronto Scarborough, Toronto, ON M1C 1A4, Canada;
| | - Rene E. Harrison
- Department of Cell & Systems Biology, University of Toronto Scarborough, Toronto, ON M1C 1A4, Canada;
- Department of Biological Sciences, University of Toronto Scarborough, Toronto, ON M1C 1A4, Canada;
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13
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Marques-Carvalho A, Silva B, Pereira FB, Kim HN, Almeida M, Sardão VA. Oestradiol and osteoclast differentiation: Effects on p53 and mitochondrial metabolism. Eur J Clin Invest 2024; 54:e14195. [PMID: 38519718 DOI: 10.1111/eci.14195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 02/05/2024] [Accepted: 02/24/2024] [Indexed: 03/25/2024]
Abstract
BACKGROUND Oestrogen deficiency increases bone resorption, contributing to osteoporosis development. Yet, the mechanisms mediating the effects of oestrogen on osteoclasts remain unclear. This study aimed to elucidate the early metabolic alteration induced by RANKL, the essential cytokine in osteoclastogenesis and 17-beta-oestradiol (E2) on osteoclast progenitor cells, using RAW 264.7 macrophage cell line and primary bone marrow-derived macrophages as biological models. RESULTS This research demonstrated that, in osteoclast precursors, RANKL stimulates complex I activity, oxidative phosphorylation (OXPHOS) and mitochondria-derived ATP production as early as 3 h of exposure. This effect on mitochondrial bioenergetics is associated with an increased capacity to oxidize TCA cycle substrates, fatty acids and amino acids. E2 inhibited all effects of RANKL on mitochondria metabolism. In the presence of RANKL, E2 also decreased cell number and stimulated the mitochondrial-mediated apoptotic pathway, detected as early as 3 h. Further, the pro-apoptotic effects of E2 during osteoclast differentiation were associated with an accumulation of p392S-p53 in mitochondria. CONCLUSIONS These findings elucidate the early effects of RANKL on osteoclast progenitor metabolism and suggest novel p53-mediated mechanisms that contribute to postmenopausal osteoporosis.
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Affiliation(s)
- Adriana Marques-Carvalho
- CNC-Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
- PhD Programme in Experimental Biology and Biomedicine (PDBEB), Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal
| | - Beatriz Silva
- Centre for Informatics and Systems, University of Coimbra, Coimbra, Portugal
| | - Francisco B Pereira
- Centre for Informatics and Systems, University of Coimbra, Coimbra, Portugal
- Polytechnic Institute of Coimbra, Coimbra Institute of Engineering, Coimbra, Portugal
| | - Ha-Neui Kim
- Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, USA
| | - Maria Almeida
- Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, USA
- Department of Orthopedic Surgery, University of Arkansas for Medical Sciences, Little Rock, USA
| | - Vilma A Sardão
- CNC-Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
- Multidisciplinary Institute of Aging (MIA-Portugal), University of Coimbra, Portugal
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14
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Miron RJ, Bohner M, Zhang Y, Bosshardt DD. Osteoinduction and osteoimmunology: Emerging concepts. Periodontol 2000 2024; 94:9-26. [PMID: 37658591 DOI: 10.1111/prd.12519] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 06/23/2023] [Accepted: 07/20/2023] [Indexed: 09/03/2023]
Abstract
The recognition and importance of immune cells during bone regeneration, including around bone biomaterials, has led to the development of an entire field termed "osteoimmunology," which focuses on the connection and interplay between the skeletal system and immune cells. Most studies have focused on the "osteogenic" capacity of various types of bone biomaterials, and much less focus has been placed on immune cells despite being the first cell type in contact with implantable devices. Thus, the amount of literature generated to date on this topic makes it challenging to extract needed information. This review article serves as a guide highlighting advancements made in the field of osteoimmunology emphasizing the role of the osteoimmunomodulatory properties of biomaterials and their impact on osteoinduction. First, the various immune cell types involved in bone biomaterial integration are discussed, including the prominent role of osteal macrophages (OsteoMacs) during bone regeneration. Thereafter, key biomaterial properties, including topography, wettability, surface charge, and adsorption of cytokines, growth factors, ions, and other bioactive molecules, are discussed in terms of their impact on immune responses. These findings highlight and recognize the importance of the immune system and osteoimmunology, leading to a shift in the traditional models used to understand and evaluate biomaterials for bone regeneration.
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Affiliation(s)
- Richard J Miron
- Department of Periodontology, University of Bern, Bern, Switzerland
| | | | - Yufeng Zhang
- Department of Oral Implantology, University of Wuhan, Wuhan, China
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15
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Kim C. Extracellular Signal-Regulated Kinases Play Essential but Contrasting Roles in Osteoclast Differentiation. Int J Mol Sci 2023; 24:15342. [PMID: 37895023 PMCID: PMC10607827 DOI: 10.3390/ijms242015342] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 10/16/2023] [Accepted: 10/17/2023] [Indexed: 10/29/2023] Open
Abstract
Bone homeostasis is regulated by the balanced actions of osteoblasts that form the bone and osteoclasts (OCs) that resorb the bone. Bone-resorbing OCs are differentiated from hematopoietic monocyte/macrophage lineage cells, whereas osteoblasts are derived from mesenchymal progenitors. OC differentiation is induced by two key cytokines, macrophage colony-stimulating factor (M-CSF), a factor essential for the proliferation and survival of the OCs, and receptor activator of nuclear factor kappa-B ligand (RANKL), a factor for responsible for the differentiation of the OCs. Mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases (ERKs), p38, and c-Jun N-terminal kinases, play an essential role in regulating the proliferation, differentiation, and function of OCs. ERKs have been known to play a critical role in the differentiation and activation of OCs. In most cases, ERKs positively regulate OC differentiation and function. However, several reports present conflicting conclusions. Interestingly, the inhibition of OC differentiation by ERK1/2 is observed only in OCs differentiated from RAW 264.7 cells. Therefore, in this review, we summarize the current understanding of the conflicting actions of ERK1/2 in OC differentiation.
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Affiliation(s)
- Chaekyun Kim
- BK21 Program in Biomedical Science & Engineering, Laboratory for Leukocyte Signaling Research, Department of Pharmacology, College of Medicine, Inha University, Incheon 22212, Republic of Korea
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16
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Evenepoel P, Stenvinkel P, Shanahan C, Pacifici R. Inflammation and gut dysbiosis as drivers of CKD-MBD. Nat Rev Nephrol 2023; 19:646-657. [PMID: 37488276 DOI: 10.1038/s41581-023-00736-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/19/2023] [Indexed: 07/26/2023]
Abstract
Two decades ago, Kidney Disease: Improving Global Outcomes coined the term chronic kidney disease-mineral and bone disorder (CKD-MBD) to describe the syndrome of biochemical, bone and extra-skeletal calcification abnormalities that occur in patients with CKD. CKD-MBD is a prevalent complication and contributes to the excessively high burden of fractures and cardiovascular disease, loss of quality of life and premature mortality in patients with CKD. Thus far, therapy has focused primarily on phosphate retention, abnormal vitamin D metabolism and parathyroid hormone disturbances, but these strategies have largely proved unsuccessful, thus calling for paradigm-shifting concepts and innovative therapeutic approaches. Interorgan crosstalk is increasingly acknowledged to have an important role in health and disease. Accordingly, mounting evidence suggests a role for both the immune system and the gut microbiome in bone and vascular biology. Gut dysbiosis, compromised gut epithelial barrier and immune cell dysfunction are prominent features of the uraemic milieu. These alterations might contribute to the inflammatory state observed in CKD and could have a central role in the pathogenesis of CKD-MBD. The emerging fields of osteoimmunology and osteomicrobiology add another level of complexity to the pathogenesis of CKD-MBD, but also create novel therapeutic opportunities.
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Affiliation(s)
- Pieter Evenepoel
- Laboratory of Nephrology, Department of Microbiology, Immunology, and Transplantation, KU Leuven, Herestraat, Leuven, Belgium.
| | - Peter Stenvinkel
- Department of Renal Medicine M99, Karolinska University Hospital, Stockholm, Sweden
| | - Catherine Shanahan
- British Heart Foundation Centre of Excellence, School of Cardiovascular and Metabolic Medicine and Sciences, King's College London, London, UK
| | - Roberto Pacifici
- Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory Microbiome Research Center, and Immunology and Molecular Pathogenesis Program, Emory University, Atlanta, GA, USA
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17
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Szybiak W, Kujawa B, Miedziaszczyk M, Lacka K. Effect of Growth Hormone and Estrogen Replacement Therapy on Bone Mineral Density in Women with Turner Syndrome: A Meta-Analysis and Systematic Review. Pharmaceuticals (Basel) 2023; 16:1320. [PMID: 37765128 PMCID: PMC10536543 DOI: 10.3390/ph16091320] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 08/27/2023] [Accepted: 09/11/2023] [Indexed: 09/29/2023] Open
Abstract
Osteoporosis is a serious implication of Turner syndrome (TS). Common methods for the treatment of TS are growth hormone (GHT) and estrogen replacement therapy (ERT). We examined the relationship between the treatment of TS and bone mineral density (BMD) of the lumbar spine. The purpose of our study was to show the currency of BMD states among patients with TS for treatment with GHT and ERT. We searched databases for studies published from inception to April 2023. The articles were related to TS, osteoporosis, ERT, GHT, BMD and treatment patients with TS. We applied the selection criteria: lumbar spine values at L1-L4; dual-energy X-ray absorptiometry (DXA); treatment which was applied: one group of articles: ERT and two group of articles: GHT; results performed as means ± SD. In total, 79 articles were analyzed, of which 20 studies were included and 5 were considered for meta-analysis. The total number of women in the articles selected was 71. Based on the results of the meta-analysis, the effect of ERT on BMD demonstrated a significant increase in BMD (the standardized mean difference in the random model was 0.593 g/cm2, 95% CI: 0.0705 to 1.116; p = 0.026), which showed that treatment with estrogen particularly increases bone mass during treatment, which contributes to reducing the risk of fractures. The effect of GHT on BMD demonstrated a non-significant decrease in BMD in patients with TS. The results for growth hormone show that this therapy does not improve bone density. However, our review emphasizes the beneficial effect of supplementing growth hormone (GH) on the clinical presentation of TS.
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Affiliation(s)
- Weronika Szybiak
- Students’ Scientific Section at the Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Science, 60-355 Poznan, Poland; (W.S.); (B.K.)
| | - Barbara Kujawa
- Students’ Scientific Section at the Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Science, 60-355 Poznan, Poland; (W.S.); (B.K.)
| | - Miłosz Miedziaszczyk
- Department of Nephrology, Transplantology and Internal Medicine, Poznan University of Medical Science, 60-355 Poznan, Poland;
| | - Katarzyna Lacka
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Science, 60-355 Poznan, Poland
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18
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Lu Y, Zhang M, Zhang J, Jiang M, Bai G. Psoralen prevents the inactivation of estradiol and treats osteoporosis via covalently targeting HSD17B2. JOURNAL OF ETHNOPHARMACOLOGY 2023; 311:116426. [PMID: 36997132 DOI: 10.1016/j.jep.2023.116426] [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: 11/04/2022] [Revised: 02/22/2023] [Accepted: 03/21/2023] [Indexed: 06/19/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Psoralea corylifolia L. seeds (P. corylifolia), popularly known as Buguzhi in traditional Chinese medicine, are often used to treat osteoporosis in China. Psoralen (Pso) is the key anti-osteoporosis constituent in P. corylifolia, however, its targets and mechanism of action are still unclear. AIM OF THE STUDY The purpose of this study was to explore the interaction between Pso and 17-β hydroxysteroid dehydrogenase type 2 (HSD17B2), an estrogen synthesis-related protein that inhibits the inactivation of estradiol (E2) to treat osteoporosis. MATERIALS AND METHODS Tissue distribution of Pso was analyzed by in-gel imaging after oral administration of an alkynyl-modified Pso probe (aPso) in mice. The target of Pso in the liver was identified and analyzed using chemical proteomics. Co-localization and cellular thermal shift assays (CETSA) were used to verify the key action targets. To detect the key pharmacophore of Pso, the interaction of Pso and its structural analogs with HSD17B2 was investigated by CETSA, HSD17B2 activity assay, and in-gel imaging determination. Target competitive test, virtual docking, mutated HSD17B2 activity, and CETSA assay were used to identify the binding site of Pso with HSD17B2. A mouse model of osteoporosis was established by ovariectomies, and the efficacy of Pso in vivo was confirmed by micro-CT, H&E staining, HSD17B2 activity, and bone-related biochemical assays. RESULTS Pso regulated estrogen metabolism by targeting HSD17B2 in the liver, with the α, β-unsaturated ester in Pso being the key pharmacophore. Pso significantly suppressed HSD17B2 activity by irreversibly binding to Lys236 of HSD17B2 and preventing NAD+ from entering the binding pocket. In vivo studies in ovariectomized mice revealed that Pso could inhibit HSD17B2 activity, prevent the inactivation of E2, increase levels of endogenous estrogen, improve bone metabolism-related indices, and play a role in anti-osteoporosis. CONCLUSIONS Pso covalently binds to Lys236 of HSD17B2 in hepatocytes to prevent the inactivation of E2, thereby aiding in the treatment of osteoporosis.
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Affiliation(s)
- Yujie Lu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, China
| | - Man Zhang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, China
| | - Jin Zhang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, China
| | - Min Jiang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, China.
| | - Gang Bai
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, China.
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Marques-Carvalho A, Sardão VA, Kim HN, Almeida M. ECSIT is essential for RANKL-induced stimulation of mitochondria in osteoclasts and a target for the anti-osteoclastogenic effects of estrogens. Front Endocrinol (Lausanne) 2023; 14:1110369. [PMID: 37152948 PMCID: PMC10157190 DOI: 10.3389/fendo.2023.1110369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 03/27/2023] [Indexed: 05/09/2023] Open
Abstract
Introduction Estrogens inhibit bone resorption and preserve bone mass, at least in part, via direct effects on osteoclasts. The binding of RANKL, the critical cytokine for osteoclast differentiation, to its receptor in osteoclast precursor cells of the monocyte lineage recruits the adaptor protein TRAF6 and activates multiple signaling pathways. Early effects of RANKL include stimulation of mitochondria. 17β-estradiol (E2) prevents the effects of RANKL on mitochondria and promotes mitochondria mediated apoptotic cell death. However, the molecular mechanisms responsible for the actions of RANKL and estrogens on mitochondria remain unknown. Evolutionarily Conserved Signaling Intermediate in Toll Pathway (ECSIT) is a complex I-associated protein that regulates immune responses in macrophages following the engagement of Toll-like receptors, which also recruit TRAF6. Here, we examined whether ECSIT could be implicated in the rapid effects of RANKL and E2 on osteoclast progenitors. Methods Bone marrow-derived macrophages (BMMs) from C57BL/6 mice were cultured with RANKL (30 ng/ml) with or without E2 (10-8 M). ECSIT-TRAF6 interaction was evaluated by co-immunoprecipitation and ECSIT levels in mitochondria and cytosolic fractions by Western blot. ShRNA lentivirus particles were used to knockdown ECSIT. Osteoclasts were enumerated after tartrate-resistant acid phosphatase staining. Oxygen consumption and extracellular acidification rates were measured with Seahorse XFe96 Analyzer. ATP, lactate, and NAD/NADH were measured with commercial assay kits. NADH oxidation to NAD was used to evaluate Complex I activity. Total and mitochondrial ROS, and mitochondrial membrane potential were measured with H2DCFDA, MitoSOX, and TMRM probes, respectively. Degradation of DEVD-AFC was used to measure Caspase-3 activity. Results We found that RANKL promoted ECSIT-TRAF6 interaction and increased the levels of ECSIT in mitochondria. E2 abrogated these effects of RANKL. Silencing of ECSIT decreased osteoclast differentiation and abrogated the inhibitory effects of E2 on osteoclastogenesis. Loss of ECSIT decreased complex I activity, oxygen consumption, NAD+/NADH redox ratio, and ATP production and increased mitochondrial ROS. In the absence of ECSIT, the stimulatory actions of RANKL on complex I activity and all other markers of oxidative phosphorylation, as well as their inhibition by E2, were prevented. Instead, RANKL stimulated apoptosis of osteoclast progenitors. Discussion These findings suggest that dysregulated mitochondria cause a switch in RANKL signaling from pro-survival to pro-apoptotic. In addition, our results indicate that ECSIT represents a central node for the early effects of RANKL on mitochondria and that inhibition of ECSIT-mediated mitochondria stimulation might contribute to the bone protective actions of estrogens.
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Affiliation(s)
- Adriana Marques-Carvalho
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
- PhD Program in Experimental Biology and Biomedicine (PDBEB), Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal
| | - Vilma A. Sardão
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
- Multidisciplinary Institute of Aging (MIA-Portugal), University of Coimbra, Coimbra, Portugal
| | - Ha-Neui Kim
- Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- Center for Musculoskeletal Disease Research, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Maria Almeida
- Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- Center for Musculoskeletal Disease Research, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- Department of Orthopedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, United States
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20
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Immune microenvironment: novel perspectives on bone regeneration disorder in osteoradionecrosis of the jaws. Cell Tissue Res 2023; 392:413-430. [PMID: 36737519 DOI: 10.1007/s00441-023-03743-z] [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: 06/23/2022] [Accepted: 01/18/2023] [Indexed: 02/05/2023]
Abstract
Osteoradionecrosis of the jaws (ORNJ) is a severe complication that occurs after radiotherapy of head and neck malignancies. Clinically, conservative treatments and surgeries for ORNJ exhibited certain therapeutic effects, whereas the regenerative disorder of the post-radiation jaw remains a pending problem to be solved. In recent years, the recognition of the role of the immune microenvironment has led to a shift from an osteoblasts (OBs) or bone marrow mesenchymal stromal cells (BMSCs)-centered view of bone regeneration to the concept of a complicated microecosystem that supports bone regeneration. Current advances in osteoimmunology have uncovered novel targets within the immune microenvironment to help improve various regeneration therapies, notably therapies potentiating the interaction between BMSCs and immune cells. However, these researches lack a thorough understanding of the immune microenvironment and the interaction network of immune cells in the course of bone regeneration, especially for the post-operative defect of ORNJ. This review summarized the composition of the immune microenvironment during bone regeneration, how the immune microenvironment interacts with the skeletal system, and discussed existing and potential strategies aimed at targeting cellular and molecular immune microenvironment components.
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Abstract
Changes in bone architecture and metabolism with aging increase the likelihood of osteoporosis and fracture. Age-onset osteoporosis is multifactorial, with contributory extrinsic and intrinsic factors including certain medical problems, specific prescription drugs, estrogen loss, secondary hyperparathyroidism, microenvironmental and cellular alterations in bone tissue, and mechanical unloading or immobilization. At the histological level, there are changes in trabecular and cortical bone as well as marrow cellularity, lineage switching of mesenchymal stem cells to an adipogenic fate, inadequate transduction of signals during skeletal loading, and predisposition toward senescent cell accumulation with production of a senescence-associated secretory phenotype. Cumulatively, these changes result in bone remodeling abnormalities that over time cause net bone loss typically seen in older adults. Age-related osteoporosis is a geriatric syndrome due to the multiple etiologies that converge upon the skeleton to produce the ultimate phenotypic changes that manifest as bone fragility. Bone tissue is dynamic but with tendencies toward poor osteoblastic bone formation and relative osteoclastic bone resorption with aging. Interactions with other aging physiologic systems, such as muscle, may also confer detrimental effects on the aging skeleton. Conversely, individuals who maintain their BMD experience a lower risk of fractures, disability, and mortality, suggesting that this phenotype may be a marker of successful aging. © 2023 American Physiological Society. Compr Physiol 13:4355-4386, 2023.
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Affiliation(s)
- Robert J Pignolo
- Department of Medicine, Divisions of Geriatric Medicine and Gerontology, Endocrinology, and Hospital Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.,The Department of Physiology and Biomedical Engineering, and the Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA
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22
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Cappariello A, Muraca M, Teti A, Rucci N. Circulating Extracellular Vesicles Express Receptor Activator of Nuclear Factor κB Ligand and Other Molecules Informative of the Bone Metabolic Status of Mouse Models of Experimentally Induced Osteoporosis. Calcif Tissue Int 2023; 112:74-91. [PMID: 36282293 PMCID: PMC9813163 DOI: 10.1007/s00223-022-01032-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 10/11/2022] [Indexed: 01/09/2023]
Abstract
Extracellular vesicles (EVs) are potent means of cell-to-cell communication. They are released in biological fluids, including blood, urine, and saliva, and can be exploited to identify new biomarkers of diseases. We hypothesized that EVs contain molecular cargos involved in bone metabolism, possibly mirroring biological differences between postmenopausal and disuse osteoporosis. We tested this hypothesis in primary murine osteoblasts subjected to steroid depletion or to unloading, and in the serum of animal models of osteoporosis induced by ovariectomy or hindlimb tail suspension. EVs were isolated by ultracentrifugation and analysed by transmission electron microscopy, cytofluorimetry, immunoblotting and RT-PCR. Large-scale analyses were performed by Real-Time arrays and Proteome Profiler™ Antibody arrays. Finally, precise titration of analytes was carried out by ELISA assay. In vitro, we confirmed an increased release of EVs enriched in surface RANKL by primary mouse osteoblasts subjected to steroid depletion or simulated microgravity compared to controls. In vivo, circulating EVs isolated from the sera of control female mice expressed RANKL along with other genes associated with bone metabolism. Serum EVs from ovariectomized or hindlimb tail-suspended mice showed distinct molecular profiles. They expressed RANKL with different kinetics, while transcriptomic and proteomic profiles uncovered unique molecular signatures that discriminated the two conditions, unveiling exclusive molecules expressed in time- and osteoporosis type-dependent manner. These results suggest that circulating EVs could represent a new tool for monitoring the onset and the progression of diverse types of the disease in mice, paving the way for their exploitation to diagnose human osteoporosis in liquid biopsies.
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Affiliation(s)
- Alfredo Cappariello
- Research Laboratories, Department of Onco-Haematology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Via Vetoio - Coppito 2, 67100, L'Aquila, Italy
| | - Maurizio Muraca
- Department of Women's and Children's Health, University of Padua, Padua, Italy
| | - Anna Teti
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Via Vetoio - Coppito 2, 67100, L'Aquila, Italy.
| | - Nadia Rucci
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Via Vetoio - Coppito 2, 67100, L'Aquila, Italy
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23
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Dong L, Teh DBL, Kennedy BK, Huang Z. Unraveling female reproductive senescence to enhance healthy longevity. Cell Res 2023; 33:11-29. [PMID: 36588114 PMCID: PMC9810745 DOI: 10.1038/s41422-022-00718-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 08/19/2022] [Indexed: 01/03/2023] Open
Abstract
In a society where women often want successful careers and equal opportunities to men, the early nature of ovarian aging often forces women to make difficult life choices between career and family development. Fertility in women begins to decline after the age of 37 years and it is rare for pregnancies to occur after 45. This reproductive decline in women is inevitable and culminates in menopause, which is a major driver of age-related diseases. In a world where biomedical advances are leading to modifiable biological outcomes, it is time to focus on mitigating female reproductive senescence to maintain fertility and preserve age-related hormonal functions, with the goal of providing increased life choices and enhancing healthspan. To date, reproductive longevity research remains an understudied field. More needs to be done to unravel the biology of the ovarian follicles, which are the functional units of reproductive lifespan and are comprised of cell types including the oocyte (female gamete) and a group of specialized supporting somatic cells. Biological attempts to maintain the quality and quantity of follicles in animal models through manipulating pathways involved in aging can potentially prolong female reproductive lifespan and healthspan. Here, we summarize the molecular events driving ovarian aging and menopause and the interventional strategies to offset these events. Developing solutions to female reproductive senescence will open doors to discover ways to enhance true healthy longevity for both men and women.
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Affiliation(s)
- Lu Dong
- Integrative Sciences and Engineering Programme, NUS Graduate School, National University of Singapore, Singapore, Singapore
- NUS Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Daniel Boon Loong Teh
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Bia Echo Asia Centre for Reproductive Longevity and Equality, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Brian Keith Kennedy
- Integrative Sciences and Engineering Programme, NUS Graduate School, National University of Singapore, Singapore, Singapore.
- NUS Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- NUS Bia Echo Asia Centre for Reproductive Longevity and Equality, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Zhongwei Huang
- NUS Bia Echo Asia Centre for Reproductive Longevity and Equality, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore.
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24
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Kim AS, Girgis CM, McDonald MM. Osteoclast Recycling and the Rebound Phenomenon Following Denosumab Discontinuation. Curr Osteoporos Rep 2022; 20:505-515. [PMID: 36201122 PMCID: PMC9718877 DOI: 10.1007/s11914-022-00756-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/19/2022] [Indexed: 01/30/2023]
Abstract
PURPOSE OF REVIEW Inhibition of receptor activator of nuclear factor kappa-B ligand (RANKL) with denosumab is an effective treatment in a number of conditions including osteoporosis where suppression of bone resorption is desired. However, denosumab discontinuation is associated with rebound increase in bone resorption and subsequent loss in bone mass and a rapid return to baseline fracture risk. We review recent data on the rebound increase in bone resorption following denosumab discontinuation and the potential mechanisms behind this phenomenon. RECENT FINDINGS Osteoclasts have been considered to be highly specialised cells that undergo apoptosis after fulfilling their function of bone resorption. However, recent studies suggest that osteoclasts are longer lived cells which migrate through vasculature and are capable of undergoing fission into a novel cell type (the osteomorph) and re-fusion in a process termed osteoclast recycling. The life cycle of the osteoclast is more complex than previously appreciated. Osteoclast recycling provides a novel mechanistic framework to examine changes in osteoclast biology in response to treatment of bone diseases and provides an exciting new avenue towards personalised medicine.
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Affiliation(s)
- Albert S Kim
- Bone Biology Program, Garvan Institute of Medical Research, Sydney, Australia
- Faculty of Medicine UNSW Sydney, St Vincent's Clinical School, Kensington, NSW, Australia
- Department of Diabetes and Endocrinology, Westmead Hospital, Westmead, NSW, Australia
| | - Christian M Girgis
- Department of Diabetes and Endocrinology, Westmead Hospital, Westmead, NSW, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
- The Westmead Institute for Medical Research, Westmead, NSW, Australia
| | - Michelle M McDonald
- Bone Biology Program, Garvan Institute of Medical Research, Sydney, Australia.
- Faculty of Medicine UNSW Sydney, St Vincent's Clinical School, Kensington, NSW, Australia.
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25
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Babu LK, Ghosh D. Looking at Mountains: Role of Sustained Hypoxia in Regulating Bone Mineral Homeostasis in Relation to Wnt Pathway and Estrogen. Clin Rev Bone Miner Metab 2022. [DOI: 10.1007/s12018-022-09283-4] [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: 11/24/2022]
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Kouthouridis S, Robson E, Hartung A, Raha S, Zhang B. Se(XY) matters: the importance of incorporating sex in microphysiological models. Trends Biotechnol 2022; 40:1284-1298. [PMID: 35597689 DOI: 10.1016/j.tibtech.2022.04.005] [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: 01/13/2022] [Revised: 04/06/2022] [Accepted: 04/09/2022] [Indexed: 01/21/2023]
Abstract
The development of microphysiological models is currently at the forefront of preclinical research. Although these 3D tissue models are being developed to mimic physiological organ function and diseases, which are often sexually dimorphic, sex is usually neglected as a biological variable. For decades, national research agencies have required government-funded clinical trials to include both male and female participants as a means of eliminating male bias. However, this is not the case in preclinical trials, which have been shown to favor male rodents in animal studies and male cell types in in vitro studies. In this Opinion, we highlight the importance of considering sex as a biological variable and outline five approaches for incorporating sex-specific features into current microphysiological models.
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Affiliation(s)
- Sonya Kouthouridis
- Department of Chemical Engineering, McMaster University, Hamilton, ON, L8S 4L8, Canada
| | - Eleanor Robson
- Department of Chemical Engineering, McMaster University, Hamilton, ON, L8S 4L8, Canada
| | - Alicia Hartung
- Department of Chemical Engineering, McMaster University, Hamilton, ON, L8S 4L8, Canada; School of Biomedical Engineering, McMaster University, Hamilton, ON, L8S 4L8, Canada
| | - Sandeep Raha
- Department of Pediatrics, McMaster University, Hamilton, ON, L8S 4L8, Canada; Graduate Program in Medical Sciences, McMaster University, Hamilton, ON, L8S 4L8, Canada.
| | - Boyang Zhang
- Department of Chemical Engineering, McMaster University, Hamilton, ON, L8S 4L8, Canada; School of Biomedical Engineering, McMaster University, Hamilton, ON, L8S 4L8, Canada.
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Gao Y, Min Q, Li X, Liu L, Lv Y, Xu W, Liu X, Wang H. Immune System Acts on Orthodontic Tooth Movement: Cellular and Molecular Mechanisms. BIOMED RESEARCH INTERNATIONAL 2022; 2022:9668610. [PMID: 36330460 PMCID: PMC9626206 DOI: 10.1155/2022/9668610] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 09/05/2022] [Accepted: 09/29/2022] [Indexed: 12/03/2022]
Abstract
Orthodontic tooth movement (OTM) is a tissue remodeling process based on orthodontic force loading. Compressed periodontal tissues have a complicated aseptic inflammatory cascade, which are considered the initial factor of alveolar bone remodeling. Since skeletal and immune systems shared a wide variety of molecules, osteoimmunology has been generally accepted as an interdisciplinary field to investigate their interactions. Unsurprisingly, OTM is considered a good mirror of osteoimmunology since it involves immune reaction and bone remolding. In fact, besides bone remodeling, OTM involves cementum resorption, soft tissue remodeling, orthodontic pain, and relapse, all correlated with immune cells and/or immunologically active substance. The aim of this paper is to review the interaction of immune system with orthodontic tooth movement, which helps gain insights into mechanisms of OTM and search novel method to short treatment period and control complications.
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Affiliation(s)
- Yajun Gao
- Department of Endodontics, Wuxi Stomatology Hospital, Wuxi, China
| | - Qingqing Min
- Department of Endodontics, Wuxi Stomatology Hospital, Wuxi, China
| | - Xingjia Li
- Department of Prosthodontics, Wuxi Stomatology Hospital, Wuxi, China
| | - Linxiang Liu
- Department of Implantology, Wuxi Stomatology Hospital, Wuxi, China
| | - Yangyang Lv
- Department of Endodontics, Wuxi Stomatology Hospital, Wuxi, China
| | - Wenjie Xu
- Department of Endodontics, Wuxi Stomatology Hospital, Wuxi, China
| | | | - Hua Wang
- Wuhu Stomatology Hospital, Wuhu, China
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Pomini KT, Buchaim DV, Bighetti ACC, Andreo JC, Rosso MPDO, Escudero JSB, Della Coletta BB, Alcalde MP, Duarte MAH, Pitol DL, Issa JPM, Ervolino E, Moscatel MBM, Bellini MZ, de Souza AT, Soares WC, Buchaim RL. Use of Photobiomodulation Combined with Fibrin Sealant and Bone Substitute Improving the Bone Repair of Critical Defects. Polymers (Basel) 2022; 14:4170. [PMID: 36236116 PMCID: PMC9572221 DOI: 10.3390/polym14194170] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/27/2022] [Accepted: 09/29/2022] [Indexed: 11/16/2022] Open
Abstract
In this preclinical protocol, an adjunct method is used in an attempt to overcome the limitations of conventional therapeutic approaches applied to bone repair of large bone defects filled with scaffolds. Thus, we evaluate the effects of photobiomodulation therapy (PBMT) on the bone repair process on defects filled with demineralized bovine bone (B) and fibrin sealant (T). The groups were BC (blood clot), BT (B + T), BCP (BC + PBMT), and BTP (B + T + PBMT). Microtomographically, BC and BCP presented a hypodense cavity with hyperdense regions adjacent to the border of the wound, with a slight increase at 42 days. BT and BTP presented discrete hyperdensing areas at the border and around the B particles. Quantitatively, BCP and BTP (16.96 ± 4.38; 17.37 ± 4.38) showed higher mean bone density volume in relation to BC and BT (14.42 ± 3.66; 13.44 ± 3.88). Histologically, BC and BCP presented deposition of immature bone at the periphery and at 42 days new bone tissue became lamellar with organized total collagen fibers. BT and BTP showed inflammatory infiltrate along the particles, but at 42 days, it was resolved, mainly in BTP. In the birefringence analysis, BT and BTP, the percentage of red birefringence increased (9.14% to 20.98% and 7.21% to 27.57%, respectively), but green birefringence was similar in relation to 14 days (3.3% to 3.5% and 3.5% to 4.2%, respectively). The number of osteocytes in the neoformed bone matrix proportionally reduced in all evaluated groups. Immunostaining of bone morphogenetic protein (BMP—2/4), osteocalcin (OCN), and vascular endothelial growth factor (VEGF) were higher in BCP and BTP when compared to the BC and BT groups (p < 0.05). An increased number of TRAP positive cells (tartrate resistant acid phosphatase) was observed in BT and BTP. We conclude that PBMT positively influenced the repair of bone defects filled with B and T.
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Affiliation(s)
- Karina Torres Pomini
- Department of Biological Sciences, Bauru School of Dentistry (FOB/USP), University of São Paulo, Bauru 17012-901, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, Postgraduate Department, University of Marilia (UNIMAR), Marilia 17525-902, Brazil
| | - Daniela Vieira Buchaim
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, Postgraduate Department, University of Marilia (UNIMAR), Marilia 17525-902, Brazil
- Teaching and Research Coordination of the Medical School, University Center of Adamantina (UNIFAI), Adamantina 17800-000, Brazil
| | - Ana Carolina Cestari Bighetti
- Department of Biological Sciences, Bauru School of Dentistry (FOB/USP), University of São Paulo, Bauru 17012-901, Brazil
| | - Jesus Carlos Andreo
- Department of Biological Sciences, Bauru School of Dentistry (FOB/USP), University of São Paulo, Bauru 17012-901, Brazil
| | | | - José Stalin Bayas Escudero
- Department of Biological Sciences, Bauru School of Dentistry (FOB/USP), University of São Paulo, Bauru 17012-901, Brazil
| | - Bruna Botteon Della Coletta
- Department of Biological Sciences, Bauru School of Dentistry (FOB/USP), University of São Paulo, Bauru 17012-901, Brazil
| | - Murilo Priori Alcalde
- Department of Dentistry, Endodontics and Dental Materials, Bauru School of Dentistry, University of São Paulo (FOB/USP), Bauru 17012-901, Brazil
| | - Marco Antonio Hungaro Duarte
- Department of Dentistry, Endodontics and Dental Materials, Bauru School of Dentistry, University of São Paulo (FOB/USP), Bauru 17012-901, Brazil
| | - Dimitrius Leonardo Pitol
- Department of Basic and Oral Biology, School of Dentistry of Ribeirão Preto, University of São Paulo (FORP/USP), Ribeirão Preto 14040-904, Brazil
| | - João Paulo Mardegan Issa
- Department of Basic and Oral Biology, School of Dentistry of Ribeirão Preto, University of São Paulo (FORP/USP), Ribeirão Preto 14040-904, Brazil
| | - Edilson Ervolino
- Department of Basic Sciences, School of Dentistry, São Paulo State University (UNESP), Araçatuba 16066-840, Brazil
| | | | - Márcia Zilioli Bellini
- Pro-Rectory of Research and Graduate Studies, University Center of Adamantina (UNIFAI), Adamantina 17800-000, Brazil
| | | | - Wendel Cleber Soares
- Vice-Rector/President, University Center of Adamantina (UNIFAI), Adamantina 17800-000, Brazil
| | - Rogerio Leone Buchaim
- Department of Biological Sciences, Bauru School of Dentistry (FOB/USP), University of São Paulo, Bauru 17012-901, Brazil
- Graduate Program in Anatomy of Domestic and Wild Animals, Faculty of Veterinary Medicine and Animal Science, University of São Paulo (FMVZ/USP), São Paulo 05508-270, Brazil
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Xiong MF, Wu LF, Chen YH, Cao RR, Deng FY, Lei SF. Body Surface Area (BSA) is a Better Osteoporosis Associated Anthropometric Parameter Than Other Anthropometric Parameters in Elderly Population. J Clin Densitom 2022; 25:630-636. [PMID: 35346589 DOI: 10.1016/j.jocd.2022.02.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 01/21/2022] [Accepted: 02/21/2022] [Indexed: 01/05/2023]
Abstract
Body surface area (BSA) is widely used for adjusting drug dose, while few studies have yet systematically evaluated its association with osteoporosis and compared its advantage with other anthropometric parameters in osteoporotic risk prediction. A total of 10,021 Chinese individuals aged over 65 years were enrolled in our study. Bone mineral density (BMD) was measured, and demographic information was also collected. Pearson correlation analysis, receiver operating characteristic (ROC) curves and predictive analysis were performed to assess the clinical practice of BSA for osteoporosis. BSA had the strongest correlation with BMD (0.544, p < 0.001) compared with conventional anthropometric indices. Besides, BSA had the highest power in osteoporosis prediction, with an area under the curve (AUC) reaching 0.81. After incorporating BSA into the osteoporosis risk prediction model, the AUC improved from 0.82 to 0.83 (p < 0.01). We found BSA provided additional diagnostic value beyond conventional anthropometric information with continuous and category NRIs were 30.40% (p < 0.01) and 3.29% (p < 0.01), respectively, and the IDI was 1.85% (p < 0.01). BSA was positively associated with osteoporosis and showed superior discriminative ability for osteoporosis risk prediction compared with other anthropometric parameters in the Chinese elderly population.
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Affiliation(s)
- Meng-Fei Xiong
- Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, P. R. China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, P. R. China
| | - Long-Fei Wu
- Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, P. R. China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, P. R. China
| | - Yong-Hao Chen
- Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, P. R. China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, P. R. China
| | - Rong-Rong Cao
- Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, P. R. China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, P. R. China
| | - Fei-Yan Deng
- Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, P. R. China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, P. R. China
| | - Shu-Feng Lei
- Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, P. R. China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, P. R. China.
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Bhatnagar A, Kekatpure AL. Postmenopausal Osteoporosis: A Literature Review. Cureus 2022; 14:e29367. [PMID: 36299953 PMCID: PMC9586717 DOI: 10.7759/cureus.29367] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 09/20/2022] [Indexed: 11/23/2022] Open
Abstract
A substantial proportion of the population of females in India falls in the perimenopausal and postmenopausal age groups. One of the complications associated with older age in women is the weakening of bones and the fall in bone mineral density (BMD). This has a severe debilitating consequence in a woman’s life and leads to reduced quality of life along with a greater incidence of fractures. If the fracture involves the hip or the vertebrae, it can cause immobility and be devastating. Postmenopausal osteoporosis is linked with the deficiency of estrogen that occurs with the cessation of the function of the ovaries as age progresses. The function of estrogen in the bone remodeling process is very well understood after years of research; estrogen plays a part in both the formation of bone as well as the prevention of the resorption of bone. A diagnosis can be made by dual-energy X-ray absorptiometry (DEXA). It is the gold standard and can spot low bone density at particular sites. The treatment options are selected according to the severity and rate of progression and factors pertaining to each patient. All postmenopausal women should be made aware of this disorder, and they should be encouraged to cultivate a healthy lifestyle through the implementation of a proper diet and inculcation of a regular exercise routine. Smoking and drinking alcohol should be limited, and calcium and vitamin D supplementation should be started in all women of the postmenopausal age group with or without osteoporosis. In patients who have been diagnosed with the disorder, pharmacological intervention is done. Drugs should be selected based on their side effects and contradictions. Follow-up is essential, and patient compliance should be carefully monitored. This article attempts to review the existing literature on this very prevalent disorder to spread awareness about it so that all postmenopausal women can take the necessary steps to prevent the weakening of their bones, and deal with its progression.
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Zhang L, Zheng YL, Wang R, Wang XQ, Zhang H. Exercise for osteoporosis: A literature review of pathology and mechanism. Front Immunol 2022; 13:1005665. [PMID: 36164342 PMCID: PMC9509020 DOI: 10.3389/fimmu.2022.1005665] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 08/18/2022] [Indexed: 11/13/2022] Open
Abstract
Osteoporosis (OP) is a disease that weakens bones and has a high morbidity rate worldwide, which is prevalent among the elderly, particularly, women of postmenopausal age. The dynamic balance between bone formation and resorption is necessary for normal bone metabolism. Many factors, including aging, estrogen deficiency, and prolonged immobilization, disrupt normal apoptosis, autophagy, and inflammation, leading to abnormal activation of osteoclasts, which gradually overwhelm bone formation by bone resorption. Moderate exercise as an effective non-drug treatment helps increase bone formation and helps relieve OP. The possible mechanisms are that exercise affects apoptosis and autophagy through the release of exercise-stimulated myohormone and the secretion of anti-inflammatory cytokines via mechanical force. In addition, exercise may also have an impact on the epigenetic processes involved in bone metabolism. Mechanical stimulation promotes bone marrow mesenchymal stem cells (BMSCs) to osteogenic differentiation by altering the expression of non-coding RNAs. Besides, by reducing DNA methylation, the mechanical stimulus can also alter the epigenetic status of osteogenic genes and show associated increased expression. In this review, we reviewed the possible pathological mechanisms of OP and summarized the effects of exercise on bone metabolism, and the mechanisms by which exercise alleviates the progression of OP, to provide a reference for the prevention and treatment of OP.
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Affiliation(s)
- Lin Zhang
- Department of Sport Rehabilitation, Shanghai University of Sport, Shanghai, China
| | - Yi-Li Zheng
- Department of Sport Rehabilitation, Shanghai University of Sport, Shanghai, China
| | - Rui Wang
- Department of Sport Rehabilitation, Shanghai University of Sport, Shanghai, China
| | - Xue-Qiang Wang
- Department of Sport Rehabilitation, Shanghai University of Sport, Shanghai, China
- Department of Rehabilitation Medicine, Shanghai Shangti Orthopaedic Hospital, Shanghai, China
- *Correspondence: Xue-Qiang Wang, ; Hao Zhang,
| | - Hao Zhang
- Department of Orthopedics, Changhai Hospital Affiliated to the Navy Military Medical University, Shanghai, China
- *Correspondence: Xue-Qiang Wang, ; Hao Zhang,
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Tanaka M, Fujii S, Inoue H, Takahashi N, Ishimi Y, Uehara M. (S)-Equol Is More Effective than (R)-Equol in Inhibiting Osteoclast Formation and Enhancing Osteoclast Apoptosis, and Reduces Estrogen Deficiency-Induced Bone Loss in Mice. J Nutr 2022; 152:1831-1842. [PMID: 35675296 DOI: 10.1093/jn/nxac130] [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: 02/27/2022] [Revised: 04/27/2022] [Accepted: 06/01/2022] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Equol, a metabolite of daidzein, binds to the estrogen receptor with greater affinity than daidzein and exhibits various biological properties. It exists as an enantiomer, either (S)-equol or (R)-equol. OBJECTIVES We have previously shown that the inhibitory effect of (S)-equol on bone fragility is stronger than that of racemic equol in ovariectomized (OVX) mice; however, the effect of (R)-equol has not been elucidated. The aim of this study was to compare the activities of equol enantiomers on bone metabolism in vitro and in vivo. METHODS Bone marrow cells (BMCs) and RAW 264.7 cells were treated with equol enantiomers. The number of osteoclasts and caspase-3/7 activity were measured. We examined the effect of equol enantiomers on osteoblast differentiation in MC3T3-E1 cells. In vivo, 8-wk-old female ddY mice were assigned to 4 groups: sham-operated (sham), OVX, OVX + 0.5 mg/d of (S)-equol (S-eq), and OVX + 0.5 mg/d of (R)-equol (R-eq). Four weeks after the intervention, femoral bone mineral density (BMD) and osteoclastic gene expression were analyzed, along with concentrations of equol enantiomers in the serum and tissues. RESULTS (S)-equol and (R)-equol inhibited osteoclast differentiation in BMCs (97% and 60%, P < 0.05) and RAW 264.7 cells (83% and 68%, P < 0.05). (S)-equol promoted apoptosis of mature osteoclasts by inducing caspase-3/7 activity (29%, P < 0.05) and enhanced osteoblast differentiation (29%, P < 0.05). In OVX mice, BMD was ameliorated in (S)-equol-treated mice (11%, P < 0.05), but not in (R)-equol-treated mice. The concentrations of (S)-equol were greater than those of (R)-equol in the serum, tibia, liver, and kidney (by 148%, 80%, 22%, and 139%, respectively). CONCLUSIONS These results suggest that (S)-equol is more effective than (R)-equol in inhibiting osteoclast formation and enhancing osteoclast apoptosis in vitro, supporting the beneficial effect of (S)-equol to reduce estrogen deficiency-induced bone loss in OVX mice.
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Affiliation(s)
- Miori Tanaka
- Department of Nutritional Science and Food Safety, Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo, Japan
| | - Shungo Fujii
- Department of Health and Nutrition, Faculty of Human Sciences, Hokkaido Bunkyo University, Eniwa, Japan
| | - Hirofumi Inoue
- Department of Nutritional Science and Food Safety, Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo, Japan
| | - Nobuyuki Takahashi
- Department of Nutritional Science and Food Safety, Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo, Japan
| | - Yoshiko Ishimi
- Research Institute, Tokyo University of Agriculture, Tokyo, Japan
| | - Mariko Uehara
- Department of Nutritional Science and Food Safety, Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo, Japan
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Jörg DJ, Fuertinger DH, Cherif A, Bushinsky DA, Mermelstein A, Raimann JG, Kotanko P. Modeling osteoporosis to design and optimize pharmacological therapies comprising multiple drug types. eLife 2022; 11:76228. [PMID: 35942681 PMCID: PMC9363122 DOI: 10.7554/elife.76228] [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: 12/08/2021] [Accepted: 06/26/2022] [Indexed: 11/13/2022] Open
Abstract
For the treatment of postmenopausal osteoporosis, several drug classes with different mechanisms of action are available. Since only a limited set of dosing regimens and drug combinations can be tested in clinical trials, it is currently unclear whether common medication strategies achieve optimal bone mineral density gains or are outperformed by alternative dosing schemes and combination therapies that have not been explored so far. Here, we develop a mathematical framework of drug interventions for postmenopausal osteoporosis that unifies fundamental mechanisms of bone remodeling and the mechanisms of action of four drug classes: bisphosphonates, parathyroid hormone analogs, sclerostin inhibitors, and receptor activator of NF-κB ligand inhibitors. Using data from several clinical trials, we calibrate and validate the model, demonstrating its predictive capacity for complex medication scenarios, including sequential and parallel drug combinations. Via simulations, we reveal that there is a large potential to improve gains in bone mineral density by exploiting synergistic interactions between different drug classes, without increasing the total amount of drug administered.
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Affiliation(s)
- David J Jörg
- Biomedical Modeling and Simulation Group, Global Research and Development, Fresenius Medical Care Germany, Bad Homburg, Germany
| | - Doris H Fuertinger
- Biomedical Modeling and Simulation Group, Global Research and Development, Fresenius Medical Care Germany, Bad Homburg, Germany
| | | | - David A Bushinsky
- Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, United States
| | | | | | - Peter Kotanko
- Renal Research Institute, New York, United States.,Icahn School of Medicine at Mount Sinai, New York, United States
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Watanabe M, Yahagi T, Shirayama T, Miyake K, Kotani H, Ogawa T, Matsuzaki K. Effects of a Whole Plant Extract of Scutellaria rubropunctata var. rubropunctata on Bone Metabolism with Estrogen Receptor Activation. PLANTS 2022; 11:plants11162075. [PMID: 36015379 PMCID: PMC9412382 DOI: 10.3390/plants11162075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/05/2022] [Accepted: 08/06/2022] [Indexed: 11/16/2022]
Abstract
We screened natural resources for estrogen receptor (ER)-activating and bone metabolism-promoting activities with the aim of finding potential treatments for osteoporosis. A screen of 1531 extracts from Ryukyu Arc plants using a luciferase reporter assay identified an 80% MeOH extract of Scutellaria rubropunctata var. rubropunctata (SRE) with dose-dependent ER transcription-promoting activity. Importantly, SRE had no proliferative effect on human breast cancer cells. SRE enhanced the ALP activity of pre-osteoblast MC3T3-E1 cells after 72 h in culture and slightly enhanced mineralization at 14 and 21 d. SRE did not significantly affect the TRAP activity of RAW264.7 cells. Gene expression analysis in MC3T3-E1 cells by quantitative real-time PCR revealed that SRE upregulated the mRNA levels of Runx2, Osterix (Osx), Osteopontin (Opn), Osteocalcin (Ocn), Smad1, Smad4, and Smad5 at 72 h, and those of Runx2, Osx, Smad1, Smad4, and Smad5 at 21 d of osteogenic induction. Analysis of the expression levels of osteogenic markers suggested that SRE may promote osteogenic differentiation by acting at the early stage of differentiation rather than at the late stage of differentiation. These results indicate that SRE activates ER and induces osteoblast differentiation by activating Runx2 and Osx through the BMP/Smad pathway, suggesting that SRE may be useful for the prevention and treatment of postmenopausal osteoporosis.
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Affiliation(s)
- Misaki Watanabe
- Laboratory of Pharmacognosy, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi 274-8555, Chiba, Japan
| | - Tadahiro Yahagi
- Laboratory of Pharmacognosy, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi 274-8555, Chiba, Japan
- Correspondence: (T.Y.); (K.M.)
| | - Takahiro Shirayama
- Laboratory of Pharmacognosy, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi 274-8555, Chiba, Japan
| | - Katsunori Miyake
- School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji 192-0392, Tokyo, Japan
| | - Hitoshi Kotani
- Faculty of Medicine, Shimane University, 1060 Nishikawatsu-cho, Matsue 690-8504, Shimane, Japan
| | - Takuya Ogawa
- School of Pharmacy, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara 324-8501, Tochigi, Japan
| | - Keiichi Matsuzaki
- Laboratory of Pharmacognosy, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi 274-8555, Chiba, Japan
- Correspondence: (T.Y.); (K.M.)
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Ledoux C, Boaretti D, Sachan A, Müller R, Collins CJ. Clinical Data for Parametrization of In Silico Bone Models Incorporating Cell-Cytokine Dynamics: A Systematic Review of Literature. Front Bioeng Biotechnol 2022; 10:901720. [PMID: 35910035 PMCID: PMC9335409 DOI: 10.3389/fbioe.2022.901720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 06/13/2022] [Indexed: 11/13/2022] Open
Abstract
In silico simulations aim to provide fast, inexpensive, and ethical alternatives to years of costly experimentation on animals and humans for studying bone remodeling, its deregulation during osteoporosis and the effect of therapeutics. Within the varied spectrum of in silico modeling techniques, bone cell population dynamics and agent-based multiphysics simulations have recently emerged as useful tools to simulate the effect of specific signaling pathways. In these models, parameters for cell and cytokine behavior are set based on experimental values found in literature; however, their use is currently limited by the lack of clinical in vivo data on cell numbers and their behavior as well as cytokine concentrations, diffusion, decay and reaction rates. Further, the settings used for these parameters vary across research groups, prohibiting effective cross-comparisons. This review summarizes and evaluates the clinical trial literature that can serve as input or validation for in silico models of bone remodeling incorporating cells and cytokine dynamics in post-menopausal women in treatment, and control scenarios. The GRADE system was used to determine the level of confidence in the reported data, and areas lacking in reported measures such as binding site occupancy, reaction rates and cell proliferation, differentiation and apoptosis rates were highlighted as targets for further research. We propose a consensus for the range of values that can be used for the cell and cytokine settings related to the RANKL-RANK-OPG, TGF-β and sclerostin pathways and a Levels of Evidence-based method to estimate parameters missing from clinical trial literature.
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Affiliation(s)
- Charles Ledoux
- Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | | | - Akanksha Sachan
- Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
- Department of Chemical Engineering, Indian Institute of Technology Bombay, Mumbai, India
| | - Ralph Müller
- Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | - Caitlyn J. Collins
- Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
- Department for Biomedical Engineering and Mechanics, Virginia Tech, Blacksburg, VI,United States
- *Correspondence: Caitlyn J. Collins,
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Kim R, Kim SW, Kim H, Ku SY. The impact of sex steroids on osteonecrosis of the jaw. Osteoporos Sarcopenia 2022; 8:58-67. [PMID: 35832420 PMCID: PMC9263170 DOI: 10.1016/j.afos.2022.05.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 04/24/2022] [Accepted: 05/18/2022] [Indexed: 12/30/2022] Open
Abstract
Sex steroid hormones play a major role in bone homeostasis. Therefore, the use of sex hormones or drugs may increase the risk of osteonecrosis of the jaw (ONJ), a complication caused by damaged bone homeostasis. However, few are known the impact of medications changing sex hormone levels on ONJ. The pathophysiology of ONJ is not clearly understood and many hypotheses exist: cessation of bone remodeling caused by its anti-resorptive effect on osteoclasts; compromised microcirculation due to medication affecting angiogenesis, including bisphosphonate; and impairment of defense mechanism toward local infection. The use of high-dose intravenous bisphosphonate in cancer patients is associated with a high prevalence of ONJ. Exogenous estrogen or androgen replacement was reported to be associated with ONJ. Polycystic ovarian syndrome (PCOS) patients demonstrate an androgen excess status, and androgen overproduction serves as a protective factor in the bone mineral density of young women. To date, there are no reports of ONJ occurrence due to androgen overproduction. In contrast, few reports on the occurrence of ONJ due to estrogen deficiency induced by drugs, such as selective estrogen receptor modulator (SERM), aromatase inhibitors, and gonadotropin-releasing hormone (GnRH) agonists, are available. Thus, the role of sex steroids in the development of ONJ is not known. Further studies are required to demonstrate the exact role of sex steroids in bone homeostasis and ONJ progression. In this review, we will discuss the relationship between medication associated with sex steroids and ONJ.
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Affiliation(s)
- Ranhee Kim
- Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul, South Korea
- Department of Obstetrics and Gynecology, Dongguk University Ilsan Medical Center, Goyang, South Korea
| | - Sung Woo Kim
- Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul, South Korea
| | - Hoon Kim
- Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul, South Korea
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, South Korea
- Institute of Reproductive Medicine and Population, Medical Research Center, Seoul National University, Seoul, 03080, South Korea
| | - Seung-Yup Ku
- Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul, South Korea
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, South Korea
- Institute of Reproductive Medicine and Population, Medical Research Center, Seoul National University, Seoul, 03080, South Korea
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Yang C, Dong Z, Ling Z, Chen Y. The crucial mechanism and therapeutic implication of RNA methylation in bone pathophysiology. Ageing Res Rev 2022; 79:101641. [PMID: 35569786 DOI: 10.1016/j.arr.2022.101641] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 04/19/2022] [Accepted: 05/09/2022] [Indexed: 12/12/2022]
Abstract
Methylation is the most common posttranscriptional modification in cellular RNAs, which has been reported to modulate the alteration of RNA structure for initiating relevant functions such as nuclear translocation and RNA degradation. Recent studies found that RNA methylation especially N6-methyladenosine (m6A) regulates the dynamic balance of bone matrix and forms a complicated network in bone metabolism. The modulation disorder of RNA methylation contributes to several pathological bone diseases including osteoporosis (OP), osteoarthritis (OA), rheumatoid arthritis (RA), and so on. In the review, we will discuss advanced technologies for detecting RNA methylation, summarize RNA methylation-related biological impacts on regulating bone homeostasis and pathological bone diseases. In addition, we focus on the promising roles of RNA methylation in early diagnosis and therapeutic implications for bone-related diseases. Then, we aim to establish a theoretical basis for further investigation in this meaningful field.
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Carletti A, Cardoso C, Lobo-Arteaga J, Sales S, Juliao D, Ferreira I, Chainho P, Dionísio MA, Gaudêncio MJ, Afonso C, Lourenço H, Cancela ML, Bandarra NM, Gavaia PJ. Antioxidant and Anti-inflammatory Extracts From Sea Cucumbers and Tunicates Induce a Pro-osteogenic Effect in Zebrafish Larvae. Front Nutr 2022; 9:888360. [PMID: 35614979 PMCID: PMC9125325 DOI: 10.3389/fnut.2022.888360] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 03/31/2022] [Indexed: 12/24/2022] Open
Abstract
Bone metabolic disorders such as osteoporosis are characterized by the loss of mineral from the bone tissue leading to its structural weakening and increased susceptibility to fractures. A growing body of evidence suggests that inflammation and oxidative stress play an important role in the pathophysiological processes involved in the rise of these conditions. As the currently available therapeutic strategies are often characterized by toxic effects associated with their long-term use, natural antioxidants and anti-inflammatory compounds such as polyphenols promise to be a valuable alternative for the prevention and treatment of these disorders. In this scope, the marine environment is becoming an important source of bioactive compounds with potential pharmacological applications. Here, we explored the bioactive potential of three species of holothurians (Echinodermata) and four species of tunicates (Chordata) as sources of antioxidant and anti-inflammatory compounds with a particular focus on polyphenolic substances. Hydroethanolic and aqueous extracts were obtained from animals' biomass and screened for their content of polyphenols and their antioxidant and anti-inflammatory properties. Hydroethanolic fractions of three species of tunicates displayed high polyphenolic content associated with strong antioxidant potential and anti-inflammatory activity. Extracts were thereafter tested for their capacity to promote bone formation and mineralization by applying an assay that uses the developing operculum of zebrafish (Danio rerio) to assess the osteogenic activity of compounds. The same three hydroethanolic fractions from tunicates were characterized by a strong in vivo osteogenic activity, which positively correlated with their anti-inflammatory potential as measured by COX-2 inhibition. This study highlights the therapeutic potential of polyphenol-rich hydroethanolic extracts obtained from three species of tunicates as a substrate for the development of novel drugs for the treatment of bone disorders correlated to oxidative stress and inflammatory processes.
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Affiliation(s)
- Alessio Carletti
- Faculty of Biomedical Sciences and Medicine (FCBM), University of Algarve, Faro, Portugal
- Centre of Marine Sciences, University of Algarve, Faro, Portugal
| | - Carlos Cardoso
- Division of Aquaculture, Upgrading and Bioprospection, Portuguese Institute for the Sea and Atmosphere (IPMA), Algés, Portugal
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), University of Porto, Porto, Portugal
| | - Jorge Lobo-Arteaga
- Division of Environmental Oceanography, Portuguese Institute for the Sea and Atmosphere, Algés, Portugal
- Marine and Environmental Sciences Centre (MARE), NOVA University of Lisbon, Lisbon, Portugal
| | - Sabrina Sales
- Division of Aquaculture, Upgrading and Bioprospection, Portuguese Institute for the Sea and Atmosphere (IPMA), Algés, Portugal
| | - Diana Juliao
- Division of Aquaculture, Upgrading and Bioprospection, Portuguese Institute for the Sea and Atmosphere (IPMA), Algés, Portugal
| | - Inês Ferreira
- Division of Aquaculture, Upgrading and Bioprospection, Portuguese Institute for the Sea and Atmosphere (IPMA), Algés, Portugal
| | - Paula Chainho
- Marine and Environmental Sciences Centre (MARE), NOVA University of Lisbon, Lisbon, Portugal
| | - Maria Ana Dionísio
- Marine and Environmental Sciences Centre (MARE), NOVA University of Lisbon, Lisbon, Portugal
| | - Maria J. Gaudêncio
- Division of Environmental Oceanography, Portuguese Institute for the Sea and Atmosphere, Algés, Portugal
| | - Cláudia Afonso
- Division of Aquaculture, Upgrading and Bioprospection, Portuguese Institute for the Sea and Atmosphere (IPMA), Algés, Portugal
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), University of Porto, Porto, Portugal
| | - Helena Lourenço
- Division of Aquaculture, Upgrading and Bioprospection, Portuguese Institute for the Sea and Atmosphere (IPMA), Algés, Portugal
| | - M. Leonor Cancela
- Faculty of Biomedical Sciences and Medicine (FCBM), University of Algarve, Faro, Portugal
- Centre of Marine Sciences, University of Algarve, Faro, Portugal
- Algarve Biomedical Center (ABC), University of Algarve, Faro, Portugal
- Centre for BioMedical Research (CBMR), University of Algarve, Faro, Portugal
| | - Narcisa M. Bandarra
- Division of Aquaculture, Upgrading and Bioprospection, Portuguese Institute for the Sea and Atmosphere (IPMA), Algés, Portugal
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), University of Porto, Porto, Portugal
| | - Paulo J. Gavaia
- Faculty of Biomedical Sciences and Medicine (FCBM), University of Algarve, Faro, Portugal
- Centre of Marine Sciences, University of Algarve, Faro, Portugal
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Ran C, Xiaojuan X, Wenxue G, Zhaoliang F, Hui S, Shen Q. Sexual dimorphism in the relation between sex hormones and osteoporosis in patients with type 2 diabetes mellitus. J Bone Miner Metab 2022; 40:460-467. [PMID: 35106610 DOI: 10.1007/s00774-021-01291-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 11/09/2021] [Indexed: 11/29/2022]
Abstract
INTRODUCTION To investigate the association between sex hormones and osteoporosis in type 2 diabetic mellitus (T2DM) patients. MATERIALS AND METHODS We performed a retrospective study in patients with T2DM. The patients were assigned into three groups (normal bone mineral density, osteopenia, and osteoporosis) in both sexes. The clinical characteristics, bone metabolic markers, and sex hormones were compared. The relationship between the sex hormones and osteoporosis was analyzed by ordinary regression analysis. Statistical analysis was performed using SPSS 26.0. RESULTS A total of 795 T2DM patients (446 men ≥ 50 years old and 349 postmenopausal women) were identified and analyzed. The osteoporosis group had the lowest estradiol level in men (P = 0.013) and the highest follicle-stimulating hormone (FSH) level in women (P = 0.042). In the multivariate analysis, men with lower estradiol levels (< 87.96 pmol/L) had a nearly 1.6-fold increased risk for osteoporosis than those with the higher estradiol levels (> 122.82 pmol/L). In addition, women with lower FSH (< 41.17 IU/L) had nearly 0.6-fold for osteoporosis compared to those with higher FSH (> 60.83 IU/L) after adjusting for age, duration of T2DM, body mass index, pulse pressure, creatinine clearance, glycosylated hemoglobin, fasting C-peptide, and estradiol (in FSH) or FSH (in estradiol). CONCLUSION In T2DM, the estrogen level was negatively correlated with osteoporosis in men, and the FSH level was positively correlated with the osteoporosis in women.
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Affiliation(s)
- Cui Ran
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xu Xiaojuan
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Gao Wenxue
- Medical Services Section, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
| | - Fei Zhaoliang
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
| | - Sheng Hui
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
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40
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Ahmed ASI, Sheng MHC, Lau KHW, Wilson SM, Wongworawat MD, Tang X, Ghahramanpouri M, Nehme A, Xu Y, Abdipour A, Zhang XB, Wasnik S, Baylink DJ. Calcium released by osteoclastic resorption stimulates autocrine/paracrine activities in local osteogenic cells to promote coupled bone formation. Am J Physiol Cell Physiol 2022; 322:C977-C990. [PMID: 35385325 PMCID: PMC9109806 DOI: 10.1152/ajpcell.00413.2021] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
A major cause of osteoporosis is impaired coupled bone formation. Mechanistically, both osteoclast-derived and bone-derived growth factors have been previously implicated. We hypothesize that the release of bone calcium during osteoclastic bone resorption is essential for coupled bone formation. Osteoclastic resorption increases interstitial fluid calcium locally from the normal 1.8 mM up to 5 mM. MC3T3-E1 osteoprogenitors, cultured in a 3.6 mM calcium medium, demonstrated that calcium signaling stimulated osteogenic cell proliferation, differentiation, and migration. Calcium channel knockdown studies implicated calcium channels, Cav1.2, store-operated calcium entry (SOCE), and calcium-sensing receptor (CaSR) in regulating bone cell anabolic activities. MC3T3-E1 cultured in a 3.6 mM calcium medium expressed increased gene expression of Wnt signaling and growth factors platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and bone morphogenic protein-2 (BMP 2). Our coupling model of bone formation, the Receptor activator of nuclear factor-kappa-Β ligand (RANKL) treated mouse calvaria, confirmed the role of calcium signaling in coupled bone formation by exhibiting increased gene expression for osterix and osteocalcin. Critically, dual immunocytochemistry showed that RANKL treatment increased osterix positive cells and increased fluorescence intensity of Cav1.2 and CaSR protein expression per osterix positive cell. The data established that calcium released by osteoclasts contributed to the regulation of coupled bone formation. CRISPR/Cas-9 knockout of Cav1.2 in osteoprogenitors cultured in basal calcium medium caused a >80% decrease in the expression of downstream osteogenic genes, emphasizing the large magnitude of the effect of calcium signaling. Thus, calcium signaling is a major regulator of coupled bone formation.
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Affiliation(s)
- Abu Shufian Ishtiaq Ahmed
- Department of Medicine, Division of Regenerative Medicine, Loma Linda University, Loma Linda, California, United States.,The Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, United States
| | - Matilda H C Sheng
- Department of Medicine, Division of Regenerative Medicine, Loma Linda University, Loma Linda, California, United States.,Musculoskeletal Disease Center, Jerry L. Pettis Memorial Veterans Affairs Medical Center, Loma Linda, California, United States
| | - Kin-Hing William Lau
- Musculoskeletal Disease Center, Jerry L. Pettis Memorial Veterans Affairs Medical Center, Loma Linda, California, United States
| | - Sean M Wilson
- The Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, United States
| | - M Daniel Wongworawat
- Department of Orthopaedic Surgery, Loma Linda University, Loma Linda, California, United States
| | - Xiaolei Tang
- Department of Veterinary Biomedical Sciences, College of Veterinary Medicine, Long Island University, Brookville, NY, United States
| | - Mahdis Ghahramanpouri
- Department of Medicine, Division of Regenerative Medicine, Loma Linda University, Loma Linda, California, United States
| | - Antoine Nehme
- Department of Medicine, Division of Regenerative Medicine, Loma Linda University, Loma Linda, California, United States
| | - Yi Xu
- Department of Medicine, Division of Regenerative Medicine, Loma Linda University, Loma Linda, California, United States.,Division of Hematology and Oncology, Department of Medicine, Loma Linda University and Loma Linda University Cancer Center, Loma Linda, CA, United States
| | - Amir Abdipour
- Division of Nephrology, Department of Medicine, Loma Linda University, Loma Linda, CA, United States
| | - Xiao-Bing Zhang
- Department of Neurosurgery, Loma Linda University, Loma Linda, California, United States
| | - Samiksha Wasnik
- Department of Medicine, Division of Regenerative Medicine, Loma Linda University, Loma Linda, California, United States
| | - David J Baylink
- Department of Medicine, Division of Regenerative Medicine, Loma Linda University, Loma Linda, California, United States
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Zheng Q, Wang Z, Sun Z, Wen J, Duan T, Zhang B. In vivo and in vitro performances of chitosan-coated Mg-Zn-Zr-Gd-Ca alloys as bone biodegradable materials in rat models. J Biomater Appl 2022; 36:1786-1799. [PMID: 35276054 DOI: 10.1177/08853282211052385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Mg alloys have attracted significant attention as promising biomedical materials, specifically as fixation materials for promoting fracture healing. However, their unsatisfactory corrosion resistances hinder further clinical applications and thus require attention. This study aims to determine the performance of novel chitosan-coated Mg-1Zn-0.3Zr-2Gd-1Ca alloy and its ability to promote the healing of osteoporotic fractures. Moreover, its corrosion resistance and biocompatibility were assessed. Performance degradations of the samples were measured via electrochemical tests, weight loss test and morphological analysis, and the uncoated and chitosan-coated fixations were compared based on their effects on biocompatibility via the cytotoxicity test, X-rays, and hematoxylin and eosin staining. The effect of bone growth and healing was investigated via immunohistochemical test. Results of the electrochemical tests indicated that compared with the bare body, chitosan-coated Mg-Zn-Ca-Zr-Gd alloys improved by one order of magnitude. Additionally, scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), and weight loss test demonstrated that the corrosion resistance of the chitosan-coated Mg alloy is better than that of the uncoated alloy. In addition, cytotoxicity analysis indicated that the viability and morphology of the chitosan-coated alloy groups were superior to the uncoated groups in vitro. During in vivo analysis, chitosan-coated and uncoated Mg-1Zn-0.3Zr-2Gd-1Ca alloys were implanted into ovariectomized SD female rats with osteoporotic fractures for 1, 2, and 3 weeks. No displacement and shedding were observed through X-rays, and pathological analyses proved that the material was not harmful for liver and kidney tissues. Immunohistochemistry revealed that the chitosan-coated Mg-Zn-Ca-Zr-Gd alloy material contributed to the healing of osteoporotic fractures in the SD rat models. In conclusion, this study demonstrated the chitosan-coated Mg-Zn-Ca-Zr-Gd alloys have improved corrosion resistance and biocompatibility. Moreover, the alloy was found to accelerate the healing of osteoporotic fractures in SD rat models. Therefore, it has significant potential as a fixation material for osteoporotic fractures.
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Affiliation(s)
- Qiuxia Zheng
- Department of surgery, Central Laboratory of Luoyang Central Hospital, 74623The Luoyang Central Hospital affiliated of Zhengzhou University, Luoyang, China
| | - Zhanhui Wang
- Department of surgery, Central Laboratory of Luoyang Central Hospital, 74623The Luoyang Central Hospital affiliated of Zhengzhou University, Luoyang, China
| | - Zongbin Sun
- Department of surgery, Central Laboratory of Luoyang Central Hospital, 74623The Luoyang Central Hospital affiliated of Zhengzhou University, Luoyang, China
| | - Jiuba Wen
- School of Material Science and Engine, 74623Henan University of science and technology, Luoyang, China
| | - Tinghe Duan
- Department of surgery, Central Laboratory of Luoyang Central Hospital, 74623The Luoyang Central Hospital affiliated of Zhengzhou University, Luoyang, China
| | - Bingbing Zhang
- Key Laboratory of Molecular Medicine for Liver Injury and Repair, 74623Henan University of science and technology, Luoyang, China
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The Anti-Inflammatory, Anti-Apoptotic and Antioxidant Effects of a Pomegranate-Peel Extract against Acrylamide-Induced Hepatotoxicity in Rats. Life (Basel) 2022; 12:life12020224. [PMID: 35207511 PMCID: PMC8878900 DOI: 10.3390/life12020224] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 01/27/2022] [Accepted: 01/28/2022] [Indexed: 12/04/2022] Open
Abstract
The Acrylamide is a toxic compound generated under oxidative stress arising from intracellular ROS production and induced toxicity. It is frequently used in industry and generated through the heating of tobacco and foods high in carbohydrates. The exact mechanism of its toxicity is still unclear. In this study, an extract of the peels of pomegranate (Punica granatum L.), a nutritious and visually appealing fruit with a diverse bioactive profile, was examined for its potential anti-apoptotic, antioxidant, and anti-inflammatory effects. A total of 40 adult male Wistar rats were allocated into four groups of 10 rats each: Group 1 was a negative-control group (CNT) and received normal saline; Group 2 was a positive-control acrylamide group and received acrylamide orally at a dose of 20 mg/kg/bw; in Group 3, the rats were supplemented with pomegranate-peel extract (P.P; 150 mg/kg/bw) orally on a daily basis for 3 weeks, administered simultaneously with the acrylamide treatment described for Group 2; Group 4 was a protective group, and the animals received the pomegranate-peel extract and acrylamide as stated for Groups 2 and 3, with the pomegranate-peel extract (P.P. extract) administered 1 week earlier than the acrylamide. The results indicate that acrylamide exposure increased the serum levels of AST, ALT, creatinine, interleukin-1 beta, and interleukin-6 in an extraordinary manner. In addition, it increased the lipid peroxidation marker malondialdehyde (MDA) and simultaneously weakened antioxidant biomarker activities (SOD, GSH, and catalase) and reduced the levels of interleukin-10. The pomegranate-peel extract was shown to reduce the inflammatory blood markers of interleukin-1 beta and IL-6. Glutathione peroxidase, superoxide dismutase, catalase, and interleukin-10 were all significantly elevated in comparison to the acrylamide-treatment group as a result of the significant reduction in MDA levels induced by the P.P extract. In addition, the pomegranate-peel extract normalized the cyclooxygenase-2 (COX2), transforming growth factor-beta 1 (TGF-β1), and caspase-3 levels, with a significant upregulation of the mRNA expression of heme oxygenase-1 (HO-1), nuclear factor erythroid 2 (Nrf2), and Bcl-2. Therefore, these data reveal that pomegranate peel has anti-inflammatory, antiapoptotic, free-radical-scavenging, and powerful antioxidant activity that protects against acrylamide toxicity.
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43
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Sun Y, Li J, Xie X, Gu F, Sui Z, Zhang K, Yu T. Recent Advances in Osteoclast Biological Behavior. Front Cell Dev Biol 2021; 9:788680. [PMID: 34957116 PMCID: PMC8694526 DOI: 10.3389/fcell.2021.788680] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 11/15/2021] [Indexed: 12/19/2022] Open
Abstract
With the progress of the aging population, bone-related diseases such as osteoporosis and osteoarthritis have become urgent problems. Recent studies have demonstrated the importance of osteoclasts in bone homeostasis, implying these will be an important mediator in the treatment of bone-related diseases. Up to now, several reviews have been performed on part of osteoclast biological behaviors such as differentiation, function, or apoptosis. However, few reviews have shown the complete osteoclast biology and research advances in recent years. Therefore, in this review, we focus on the origin, differentiation, apoptosis, behavior changes and coupling signals with osteoblasts, providing a simple but comprehensive overview of osteoclasts for subsequent studies.
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Affiliation(s)
- Yang Sun
- Department of Orthopedics, The First Hospital of Jilin University, Changchun, China
| | - Jiangbi Li
- Department of Orthopedics, The First Hospital of Jilin University, Changchun, China
| | - Xiaoping Xie
- Department of Orthopedics, The First Hospital of Jilin University, Changchun, China
| | - Feng Gu
- Department of Orthopedics, The First Hospital of Jilin University, Changchun, China
| | - Zhenjiang Sui
- Department of Orthopedics, The First Hospital of Jilin University, Changchun, China
| | - Ke Zhang
- Department of Orthopedics, The First Hospital of Jilin University, Changchun, China
| | - Tiecheng Yu
- Department of Orthopedics, The First Hospital of Jilin University, Changchun, China
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44
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Cheng X, Zhou X, Liu C, Xu X. Oral Osteomicrobiology: The Role of Oral Microbiota in Alveolar Bone Homeostasis. Front Cell Infect Microbiol 2021; 11:751503. [PMID: 34869060 PMCID: PMC8635720 DOI: 10.3389/fcimb.2021.751503] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 10/29/2021] [Indexed: 02/05/2023] Open
Abstract
Osteomicrobiology is a new research field in which the aim is to explore the role of microbiota in bone homeostasis. The alveolar bone is that part of the maxilla and mandible that supports the teeth. It is now evident that naturally occurring alveolar bone loss is considerably stunted in germ-free mice compared with specific-pathogen-free mice. Recently, the roles of oral microbiota in modulating host defense systems and alveolar bone homeostasis have attracted increasing attention. Moreover, the mechanistic understanding of oral microbiota in mediating alveolar bone remodeling processes is undergoing rapid progress due to the advancement in technology. In this review, to provide insight into the role of oral microbiota in alveolar bone homeostasis, we introduced the term “oral osteomicrobiology.” We discussed regulation of alveolar bone development and bone loss by oral microbiota under physiological and pathological conditions. We also focused on the signaling pathways involved in oral osteomicrobiology and discussed the bridging role of osteoimmunity and influencing factors in this process. Finally, the critical techniques for osteomicrobiological investigations were introduced.
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Affiliation(s)
- Xingqun Cheng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xuedong Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Chengcheng Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xin Xu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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45
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Abstract
PURPOSE OF REVIEW Postmenopausal osteoporosis reduces circulating estrogen levels, which leads to osteoclast resorption, bone loss, and fracture. This review addresses emerging evidence that osteoporosis is not simply a disease of bone loss but that mechanosensitive osteocytes that regulate both osteoclasts and osteoblasts are also impacted by estrogen deficiency. RECENT FINDINGS At the onset of estrogen deficiency, the osteocyte mechanical environment is altered, which coincides with temporal changes in bone tissue composition. The osteocyte microenvironment is also altered, apoptosis is more prevalent, and hypermineralization occurs. The mechanobiological responses of osteocytes are impaired under estrogen deficiency, which exacerbates osteocyte paracrine regulation of osteoclasts. Recent research reveals changes in osteocytes during estrogen deficiency that may play a critical role in the etiology of the disease. A paradigm change for osteoporosis therapy requires an advanced understanding of such changes to establish the efficacy of osteocyte-targeted therapies to inhibit resorption and secondary mineralization.
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Affiliation(s)
- Laoise M McNamara
- Mechanobiology and Medical Device Research Group, Biomedical Engineering, College of Science and Engineering, National University of Ireland, Galway, Ireland.
- Centre for Research in Medical Devices (CÚRAM), National University of Ireland, Galway, Ireland.
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46
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Qin Y, Liu Y, Jiang Y, Mei S, Liu Y, Feng J, Guo L, Du J, Graves D, Liu Y. Cigarette Smoke Exposure Inhibits Osteoclast Apoptosis via the mtROS Pathway. J Dent Res 2021; 100:1378-1386. [PMID: 33978516 PMCID: PMC8723169 DOI: 10.1177/00220345211009471] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
It is widely known that smoking is a risk factor for bone loss and plays a key role in osteopenia. Despite this well-known association, the mechanisms by which smoking affects bone have not been definitively established. Since smoking increases bone loss and potentially affects bone resorption in response to mechanical force, we investigated the impact of cigarette smoke on osteoclast numbers and underlying mechanisms in a mouse model of orthodontic tooth movement (OTM). The experimental group was exposed to once-daily cigarette smoke while the control group was not, and tooth movement distance and osteoclast numbers were assessed. In addition, the effect of cigarette smoke extract (CSE) on osteoclast precursor proliferation and osteoclast apoptosis was assessed in vitro. We found that cigarette smoke exposure enhanced bone remodeling stimulated by mechanical force and increased osteoclast numbers in vivo. Also, CSE increased the number of osteoclasts by inhibiting osteoclast apoptosis via the mitochondrial reactive oxygen species/cytochrome C/caspase 3 pathway in vitro. Moreover, exposure of mice to cigarette smoke affected bone marrow cells, leading to increased formation of osteoclasts in vitro. This study identifies a previously unknown mechanism of how smoking has a detrimental impact on bone.
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Affiliation(s)
- Y. Qin
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
| | - Y. Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
| | - Y. Jiang
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
| | - S. Mei
- Department of Stomatology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Y. Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
| | - J. Feng
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
| | - L. Guo
- Department of Orthodontics School of Stomatology, Capital Medical University, Beijing, China
| | - J. Du
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
| | - D.T. Graves
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Y. Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
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McDonald MM, Kim AS, Mulholland BS, Rauner M. New Insights Into Osteoclast Biology. JBMR Plus 2021; 5:e10539. [PMID: 34532619 PMCID: PMC8441501 DOI: 10.1002/jbm4.10539] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 07/06/2021] [Accepted: 07/17/2021] [Indexed: 12/13/2022] Open
Abstract
Osteoclasts are multinucleated cells that are characterized by their unique ability to resorb large quantities of bone. Therefore, they are frequently the target of therapeutic interventions to ameliorate bone loss. In an adult organism, osteoclasts derive from hematopoietic stem cells and differentiate into osteoclasts within a multistep process under the influence of macrophage colony‐stimulating factor (M‐CSF) and receptor activator of NF‐κB ligand (RANKL). Historically, the osteoclast life cycle has been defined as linear, whereby lineage‐committed mononuclear precursors fuse to generate multinucleated highly specialized and localized bone phagocytic cells, which then undergo apoptosis within weeks. Recent advances through lineage tracing, single cell RNA sequencing, parabiosis, and intravital imaging approaches have challenged this dogma, revealing they have greater longevity and the capacity to circulate and undergo cell recycling. Indeed, these new insights highlight that under homeostatic conditions very few incidences of osteoclast apoptosis occur. More importantly, as we revisit the formation and fate of the osteoclast, novel methods to target osteoclast biology in bone pathology and regeneration are emerging. This review briefly summarizes the historical life cycle of osteoclasts and highlights recent discoveries made through advanced methodologies, which have led to a paradigm shift in osteoclast biology. These findings are discussed in light of both existing and emerging bone targeted therapeutics, bone pathologies, and communication between osteoclasts and cells resident in bone or at distant sites. © 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)
- Michelle Maree McDonald
- Bone Biology Program, Healthy Ageing Theme Garvan Institute of Medical Research Sydney NSW Australia.,St Vincent's Clinical School Faculty of Medicine UNSW Sydney Sydney NSW Australia
| | - Albert Sungsoo Kim
- Bone Biology Program, Healthy Ageing Theme Garvan Institute of Medical Research Sydney NSW Australia.,St Vincent's Clinical School Faculty of Medicine UNSW Sydney Sydney NSW Australia.,Department of Diabetes and Endocrinology Royal North Shore Hospital St Leonards NSW Australia.,Department of Diabetes and Endocrinology Westmead Hospital Westmead NSW Australia
| | - Bridie S Mulholland
- School of Pharmacy and Medical Sciences Griffith University Gold Coast QLD Australia.,Menzies Health Institute Queensland Griffith University Gold Coast QLD Australia
| | - Martina Rauner
- Department of Medicine III Medical Faculty of the Technische Universität Dresden Dresden Germany.,Center for Healthy Aging Medical Faculty of the Technische Universität Dresden Dresden Germany
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Anwar MJ, Alenezi SK, Mahmood D, Azam F, Alharbi KS. An insight into the implications of estrogen deficiency and transforming growth factor β in antiepileptic drugs-induced bone loss. Eur J Pharmacol 2021; 907:174313. [PMID: 34245750 DOI: 10.1016/j.ejphar.2021.174313] [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: 02/04/2021] [Revised: 06/23/2021] [Accepted: 07/05/2021] [Indexed: 11/28/2022]
Abstract
There have been a number of reports that chronic antiepileptic drug (AEDs) therapy is associated with abnormal bone and calcium metabolism, osteoporosis/osteomalacia, and increased risk of fractures. Bony adverse effects of long term antiepileptic drug therapy have been reported for more than four decades but the exact molecular mechanism is still lacking. Several mechanisms have been proposed regarding AEDs induced bone loss; Hypovitaminosis D, hyperparathyroidism, estrogen deficiency, calcitonin deficiency. Transforming growth factor-β (TGF- β) is abundant in bone matrix and has been shown to regulate the activity of osteoblasts and osteoclasts in vitro. All isoforms of TGF- β are expressed in bone and intricately play role in bone homeostasis by modulating estrogen level. Ovariectomised animal have shown down regulation of TGF- β in bone that could also be a probable target of AEDs therapy associated bone loss. One of the widely accepted hypotheses regarding the conventional drugs induced bone loss is hypovitaminosis D which is by virtue of their microsomal enzyme inducing effect. However, despite of the lack of enzyme inducing effect of certain newer antiepileptic drugs, reduced bone mineral density with these drugs have also been reported. Thus an understanding of bone biology, pathophysiology of AEDs induced bone loss at molecular level can aid in the better management of bone loss in patients on chronic AEDs therapy. This review focuses mainly on certain new molecular targets of AEDs induced bone loss.
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Affiliation(s)
- Md Jamir Anwar
- Department of Pharmacology & Toxicology, Unaizah College of Pharmacy, Qassim University, Al-Qassim, Saudi Arabia.
| | - Sattam K Alenezi
- Department of Pharmacology & Toxicology, Unaizah College of Pharmacy, Qassim University, Al-Qassim, Saudi Arabia
| | - Danish Mahmood
- Department of Pharmacology & Toxicology, Unaizah College of Pharmacy, Qassim University, Al-Qassim, Saudi Arabia
| | - Faizul Azam
- Department of Pharmaceutical Chemistry & Pharmacognosy, Unaizah College of Pharmacy, Qassim University, Al-Qassim, Saudi Arabia
| | - Khalid Saad Alharbi
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakakah, Saudi Arabia
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Influence of osteoporosis and mechanical loading on bone around osseointegrated dental implants: A rodent study. J Mech Behav Biomed Mater 2021; 123:104771. [PMID: 34438251 DOI: 10.1016/j.jmbbm.2021.104771] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 08/06/2021] [Accepted: 08/08/2021] [Indexed: 11/20/2022]
Abstract
This study aimed to evaluate the influence of estrogen deficiency and mechanical loading on bone around osseointegrated dental implants in a rat jaw model. The maxillary right first molars of 36 rats were extracted. One week later, the rats were divided into an unloaded group and a loaded group; short head implants and long head implants were inserted respectively. Nine weeks after implantation, the rats were further subjected to ovariectomy (OVX) or sham surgery. All animals were euthanized 21 weeks after OVX. Micro-computed tomography, histological and histomorphometrical evaluation were undertaken. Systemic bone mineral density and bone volume fraction decreased in OVX groups compared with the sham controls. Histomorphometrical observation indicated that unloaded OVX group showed significantly damaged osseointegration and bone loss versus the loaded OVX group. Both the bone density (BD) inside the peri-implant grooves and the percentage of bone-to-implant contact (BIC) were lower in the OVX groups than in the sham-surgery groups, although mechanical loading increased the BIC and BD in the loaded OVX group compared with the unloaded OVX group. An increased number of positive cells for tartrate-resistant acid phosphatase was observed in the OVX groups versus the sham controls. The percentage of sclerostin-positive osteocytes was lower under loaded compared with unloaded conditions in both the OVX groups and the sham controls. In conclusion, estrogen deficiency could be a risk factor for the long-term stability of osseointegrated implants, while mechanical loading could attenuate the negative influence of estrogen deficiency on bone formation and osseointegration.
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50
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Saxena Y, Routh S, Mukhopadhaya A. Immunoporosis: Role of Innate Immune Cells in Osteoporosis. Front Immunol 2021; 12:687037. [PMID: 34421899 PMCID: PMC8374941 DOI: 10.3389/fimmu.2021.687037] [Citation(s) in RCA: 105] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 07/22/2021] [Indexed: 12/11/2022] Open
Abstract
Osteoporosis or porous bone disorder is the result of an imbalance in an otherwise highly balanced physiological process known as 'bone remodeling'. The immune system is intricately involved in bone physiology as well as pathologies. Inflammatory diseases are often correlated with osteoporosis. Inflammatory mediators such as reactive oxygen species (ROS), and pro-inflammatory cytokines and chemokines directly or indirectly act on the bone cells and play a role in the pathogenesis of osteoporosis. Recently, Srivastava et al. (Srivastava RK, Dar HY, Mishra PK. Immunoporosis: Immunology of Osteoporosis-Role of T Cells. Frontiers in immunology. 2018;9:657) have coined the term "immunoporosis" to emphasize the role of immune cells in the pathology of osteoporosis. Accumulated pieces of evidence suggest both innate and adaptive immune cells contribute to osteoporosis. However, innate cells are the major effectors of inflammation. They sense various triggers to inflammation such as pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), cellular stress, etc., thus producing pro-inflammatory mediators that play a critical role in the pathogenesis of osteoporosis. In this review, we have discussed the role of the innate immune cells in great detail and divided these cells into different sections in a systemic manner. In the beginning, we talked about cells of the myeloid lineage, including macrophages, monocytes, and dendritic cells. This group of cells explicitly influences the skeletal system by the action of production of pro-inflammatory cytokines and can transdifferentiate into osteoclast. Other cells of the myeloid lineage, such as neutrophils, eosinophils, and mast cells, largely impact osteoporosis via the production of pro-inflammatory cytokines. Further, we talked about the cells of the lymphoid lineage, including natural killer cells and innate lymphoid cells, which share innate-like properties and play a role in osteoporosis. In addition to various innate immune cells, we also discussed the impact of classical pro-inflammatory cytokines on osteoporosis. We also highlighted the studies regarding the impact of physiological and metabolic changes in the body, which results in chronic inflammatory conditions such as ageing, ultimately triggering osteoporosis.
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Affiliation(s)
- Yogesh Saxena
- Department of Biological Sciences, Indian Institute of Science Education and Research Mohali, Mohali, India
| | - Sanjeev Routh
- Department of Biological Sciences, Indian Institute of Science Education and Research Mohali, Mohali, India
| | - Arunika Mukhopadhaya
- Department of Biological Sciences, Indian Institute of Science Education and Research Mohali, Mohali, India
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