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Janson TM, Ramenzoni LL, Hatz CR, Schlagenhauf U, Attin T, Schmidlin PR. Limosilactobacillus reuteri supernatant attenuates inflammatory responses of human gingival fibroblasts to LPS but not to elevated glucose levels. J Periodontal Res 2024; 59:974-981. [PMID: 38764133 DOI: 10.1111/jre.13290] [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: 11/07/2023] [Revised: 05/04/2024] [Accepted: 05/05/2024] [Indexed: 05/21/2024]
Abstract
AIM We investigated the in vitro effect of Limosilactobacillus reuteri DSM 17938 supernatant on the inflammatory response of human gingival fibroblasts (HGF) challenged by lipopolysaccharide (LPS) or elevated glucose levels. METHODS HGF were exposed to LPS (1 μg/mL), glucose (5, 12 mM or 25 mM), and dilutions of supernatant prepared from L. reuteri DSM 17938 (0.5 × 107, 1.0 × 107, 2.5 × 107, and 5.0 × 107 CFU/mL). After 24 h cell viability and levels of cytokines (IL-1β, IL-6 and IL-8) and TLR-2 were determined. RESULTS None of the tested L. reuteri (DSM 17938) supernatant concentrations reduced the viability of HGF. Supernatant concentrations (2.5 × 107 and 5 × 107 CFU/mL) significantly (p < .05) decreased the production of IL-1β, IL-6, IL-8, and TLR-2 in the presence of LPS. In contrast, inflammatory markers were not reduced by L. reuteri supernatant in the presence of glucose. Glucose concentrations of 12 mM and 24 mM still lead to an elevated production of the investigated biochemical mediators. CONCLUSION While L. reuteri (DSM 17938) supernatant attenuates the inflammatory response of HGF to LPS in a dose-dependent manner, elevated glucose levels suppress this action. These in vitro results support the overall anti-inflammatory efficacy of L. reuteri supplementation in plaque-associated periodontal inflammations.
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Affiliation(s)
- T M Janson
- Division of Periodontology and Peri-implant Diseases, Clinic of Conservative and Preventive Dentistry, Center for Dental Medicine, University of Zurich, Zurich, Switzerland
| | - L L Ramenzoni
- Division of Periodontology and Peri-implant Diseases, Clinic of Conservative and Preventive Dentistry, Center for Dental Medicine, University of Zurich, Zurich, Switzerland
| | - C R Hatz
- Division of Periodontology and Peri-implant Diseases, Clinic of Conservative and Preventive Dentistry, Center for Dental Medicine, University of Zurich, Zurich, Switzerland
| | - U Schlagenhauf
- Division of Periodontology and Peri-implant Diseases, Clinic of Conservative and Preventive Dentistry, Center for Dental Medicine, University of Zurich, Zurich, Switzerland
- Department of Conservative Dentistry and Periodontology, Center for Oral Health, University Hospital Wuerzburg, Wuerzburg, Germany
| | - T Attin
- Division of Periodontology and Peri-implant Diseases, Clinic of Conservative and Preventive Dentistry, Center for Dental Medicine, University of Zurich, Zurich, Switzerland
| | - P R Schmidlin
- Division of Periodontology and Peri-implant Diseases, Clinic of Conservative and Preventive Dentistry, Center for Dental Medicine, University of Zurich, Zurich, Switzerland
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Ryan G, Magony R, Gortler H, Godbout C, Schemitsch EH, Nauth A. Systemically impaired fracture healing in small animal research: A review of fracture repair models. J Orthop Res 2021; 39:1359-1367. [PMID: 33580554 DOI: 10.1002/jor.25003] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 11/09/2020] [Accepted: 02/10/2021] [Indexed: 02/04/2023]
Abstract
Fracture healing is a complex process requiring mechanical stability, an osteoconductive matrix, and osteoinductive and osteogenic biology. This intricate process is easily disrupted by various patient factors such as chronic disease and lifestyle. As the medical complexity and age of patients with fractures continue to increase, the importance of developing relevant experimental models is becoming paramount in preclinical research. The objective of this review is to describe the most common small animal models of systemically impaired fracture healing used in the orthopedic literature including osteoporosis, diabetes mellitus, smoking, alcohol use, obesity, and ageing. This review will provide orthopedic researchers with a summary of current models of systemically impaired fracture healing used in small animals and present an overview of the methods of induction for each condition.
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Affiliation(s)
- Gareth Ryan
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, University of Toronto, Toronto, Ontario, Canada
| | - Richard Magony
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, University of Toronto, Toronto, Ontario, Canada
| | - Hilary Gortler
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, University of Toronto, Toronto, Ontario, Canada
| | - Charles Godbout
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, University of Toronto, Toronto, Ontario, Canada
| | - Emil H Schemitsch
- Department of Surgery, Division of Orthopaedic Surgery, University of Western Ontario, London, Ontario, Canada
| | - Aaron Nauth
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, University of Toronto, Toronto, Ontario, Canada.,Department of Surgery, Division of Orthopaedic Surgery, St. Michael's Hospital - Unity Health Toronto, University of Toronto, Toronto, Ontario, Canada
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Histological and Nanomechanical Properties of a New Nanometric Hydroxiapatite Implant Surface. An In Vivo Study in Diabetic Rats. MATERIALS 2020; 13:ma13245693. [PMID: 33322243 PMCID: PMC7764315 DOI: 10.3390/ma13245693] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 12/01/2020] [Accepted: 12/02/2020] [Indexed: 01/01/2023]
Abstract
Implant therapy is a predictable treatment to replace missing teeth. However, the osseointegration process may be negatively influenced by systemic conditions, such as diabetes mellitus (DM). Microtopography and implant surface developments are strategies associated to better bone repair. This study aimed to evaluate, in healthy and diabetic rats, histomorphometric (bone to implant contact = %BIC; and bone area fraction occupancy = %BAFO) and nanomechanical (elastic modulus = EM; and hardness = H) bone parameters, in response to a nanometric hydroxyapatite implant surface. Mini implants (machined = MAC; double acid etched = DAE, and with addition of nano-hydroxyapatite = NANO) were installed in tibias of healthy and diabetic rats. The animals were euthanized at 7 and 30 days. NANO surface presented higher %BIC and %BAFO when compared to MAC and DAE (data evaluated as a function of implant surface). NANO surface presented higher %BIC and %BAFO, with statistically significant differences (data as a function of time and implant surface). NANO surface depicted higher EM and H values, when compared to machined and DAE surfaces (data as a function of time and implant surface). Nano-hydroxyapatite coated implants presented promising biomechanical results and could be an important tool to compensate impaired bone healing reported in diabetics.
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Miniplates coated by plasma electrolytic oxidation improve bone healing of simulated femoral fractures on low bone mineral density rats. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2020; 120:111775. [PMID: 33545905 DOI: 10.1016/j.msec.2020.111775] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 11/09/2020] [Accepted: 11/27/2020] [Indexed: 01/19/2023]
Abstract
The treatment of polytrauma patients represents a great challenge in the maxillofacial and orthopedic surgery fields. Therefore, this study tested the hypothesis that the use of a bioactive coating (by plasma electrolytic oxidation, PEO) on titanium microplates could improve the fracture healing of low bone mineral density (BMD) rats. Thirty female rats underwent bilateral ovariectomy surgery (OVX), and 35 rats underwent fake surgery (SHAM). Three months later, animals were subjected to femoral fracture simulation and were fixed with either non-coated (CONV) or coated (PEO) titanium miniplates. Eight weeks postoperatively, microplate/bone complexes were analyzed through computed microtomography, histometric, confocal microscopy, molecular, and biomechanical analysis. Bioactive elements (Ca and P) were incorporated on the PEO microplate and the surface was modified in a volcano-like structure. In the microCT analysis the OVX/PEO group had greater values for Tb.Th (bone trabecular thickness), Tb.Sp (separation of bone trabeculae) and Tb.N (number of trabeculae) parameters compared to the OVX/CONV group. According to histometric analysis, the OVX/PEO group showed significantly higher new bone formation than the OVX/CONV group (P < 0.05). For the fluorochrome area, the OVX groups (PEO and CONV) showed greater values for calcein precipitation (old bone) than alizarin red (new bone). Molecular results showed greater values for proteins related to the final phase of bone formation (P < 0.05) in the OVX/PEO group. The OVX/PEO group showed higher bone/miniplate system resilience compared to the others (P < 0.05). It was concluded that PEO coating optimizes bone healing on simulated femoral fractures in low bone mineral density rats. This sheds new light in the treatment of osteoporotic patients with bone fractures.
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Oda T, Niikura T, Fukui T, Oe K, Kuroiwa Y, Kumabe Y, Sawauchi K, Yoshikawa R, Mifune Y, Hayashi S, Matsumoto T, Matsushita T, Kawamoto T, Sakai Y, Akisue T, Kuroda R. Transcutaneous CO 2 application accelerates fracture repair in streptozotocin-induced type I diabetic rats. BMJ Open Diabetes Res Care 2020; 8:8/2/e001129. [PMID: 33323458 PMCID: PMC7745327 DOI: 10.1136/bmjdrc-2019-001129] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 10/29/2020] [Accepted: 11/11/2020] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION Diabetes mellitus (DM) negatively affects fracture repair by inhibiting endochondral ossification, chondrogenesis, callus formation, and angiogenesis. We previously reported that transcutaneous CO2 application accelerates fracture repair by promoting endochondral ossification and angiogenesis. The present study aimed to determine whether CO2 treatment would promote fracture repair in cases with type I DM. RESEARCH DESIGN AND METHODS A closed femoral shaft fracture was induced in female rats with streptozotocin-induced type I DM. CO2 treatment was performed five times a week for the CO2 group. Sham treatment, where CO2 was replaced with air, was performed for the control group. Radiographic, histologic, genetic, and biomechanical measurements were taken at several time points. RESULTS Radiographic assessment demonstrated that fracture repair was induced in the CO2 group. Histologically, accelerated endochondral ossification and capillary formation were observed in the CO2 group. Immunohistochemical assessment indicated that early postfracture proliferation of chondrocytes in callus was enhanced in the CO2 group. Genetic assessment results suggested that cartilage and bone formation, angiogenesis, and vasodilation were upregulated in the CO2 group. Biomechanical assessment revealed enhanced mechanical strength in the CO2 group. CONCLUSIONS Our findings suggest that CO2 treatment accelerates fracture repair in type I DM rats. CO2 treatment could be an effective strategy for delayed fracture repair due to DM.
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Affiliation(s)
- Takahiro Oda
- Orthopaedic Surgery, Kobe University Graduate School of Medicine School of Medicine, Kobe, Hyogo, Japan
| | - Takahiro Niikura
- Orthopaedic Surgery, Kobe University Graduate School of Medicine School of Medicine, Kobe, Hyogo, Japan
| | - Tomoaki Fukui
- Orthopaedic Surgery, Kobe University Graduate School of Medicine School of Medicine, Kobe, Hyogo, Japan
| | - Keisuke Oe
- Orthopaedic Surgery, Kobe University Graduate School of Medicine School of Medicine, Kobe, Hyogo, Japan
| | - Yu Kuroiwa
- Orthopaedic Surgery, Kobe University Graduate School of Medicine School of Medicine, Kobe, Hyogo, Japan
| | - Yohei Kumabe
- Orthopaedic Surgery, Kobe University Graduate School of Medicine School of Medicine, Kobe, Hyogo, Japan
| | - Kenichi Sawauchi
- Orthopaedic Surgery, Kobe University Graduate School of Medicine School of Medicine, Kobe, Hyogo, Japan
| | - Ryo Yoshikawa
- Orthopaedic Surgery, Kobe University Graduate School of Medicine School of Medicine, Kobe, Hyogo, Japan
| | - Yutaka Mifune
- Orthopaedic Surgery, Kobe University Graduate School of Medicine School of Medicine, Kobe, Hyogo, Japan
| | - Shinya Hayashi
- Orthopaedic Surgery, Kobe University Graduate School of Medicine School of Medicine, Kobe, Hyogo, Japan
| | - Tomoyuki Matsumoto
- Orthopaedic Surgery, Kobe University Graduate School of Medicine School of Medicine, Kobe, Hyogo, Japan
| | - Takehiko Matsushita
- Orthopaedic Surgery, Kobe University Graduate School of Medicine School of Medicine, Kobe, Hyogo, Japan
| | - Teruya Kawamoto
- Orthopaedic Surgery, Kobe University Graduate School of Medicine School of Medicine, Kobe, Hyogo, Japan
| | - Yoshitada Sakai
- Division of Rehabilitation Medicine, Kobe University Graduate School of Medicine School of Medicine, Kobe, Hyogo, Japan
| | - Toshihiro Akisue
- Department of Rehabilitation Science, Kobe University Faculty of Health Sciences and Graduate School of Medicine Faculty of Health Sciences, Kobe, Hyogo, Japan
| | - Ryosuke Kuroda
- Orthopaedic Surgery, Kobe University Graduate School of Medicine School of Medicine, Kobe, Hyogo, Japan
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Administration of Human Non-Diabetic Mesenchymal Stromal Cells to a Murine Model of Diabetic Fracture Repair: A Pilot Study. Cells 2020; 9:cells9061394. [PMID: 32503335 PMCID: PMC7348854 DOI: 10.3390/cells9061394] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 05/27/2020] [Accepted: 05/29/2020] [Indexed: 01/05/2023] Open
Abstract
Individuals living with type 1 diabetes mellitus may experience an increased risk of long bone fracture. These fractures are often slow to heal, resulting in delayed reunion or non-union. It is reasonable to theorize that the underlying cause of these diabetes-associated osteopathies is faulty repair dynamics as a result of compromised bone marrow progenitor cell function. Here it was hypothesized that the administration of non-diabetic, human adult bone marrow-derived mesenchymal stromal cells (MSCs) would enhance diabetic fracture healing. Human MSCs were locally introduced to femur fractures in streptozotocin-induced diabetic mice, and the quality of de novo bone was assessed eight weeks later. Biodistribution analysis demonstrated that the cells remained in situ for three days following administration. Bone bridging was evident in all animals. However, a large reparative callus was retained, indicating non-union. µCT analysis elucidated comparable callus dimensions, bone mineral density, bone volume/total volume, and volume of mature bone in all groups that received cells as compared to the saline-treated controls. Four-point bending evaluation of flexural strength, flexural modulus, and total energy to re-fracture did not indicate a statistically significant change as a result of cellular administration. An ex vivo lymphocytic proliferation recall assay indicated that the xenogeneic administration of human cells did not result in an immune response by the murine recipient. Due to this dataset, the administration of non-diabetic bone marrow-derived MSCs did not support fracture healing in this pilot study.
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Alder KD, White AHA, Chung Y, Lee I, Back J, Kwon H, Cahill SV, Hao Z, Li L, Chen F, Lee S, Riedel MD, Lee FY. Systemic Parathyroid Hormone Enhances Fracture Healing in Multiple Murine Models of Type 2 Diabetes Mellitus. JBMR Plus 2020; 4:e10359. [PMID: 32382692 PMCID: PMC7202418 DOI: 10.1002/jbm4.10359] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 02/28/2020] [Accepted: 03/07/2020] [Indexed: 12/30/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a multisystemic disease that afflicts more than 415 million people globally-the incidence and prevalence of T2DM continues to rise. It is well-known that T2DM has detrimental effects on bone quality that increase skeletal fragility, which predisposes subjects to an increased risk of fracture and fracture healing that results in non- or malunion. Diabetics have been found to have perturbations in metabolism, hormone production, and calcium homeostasis-particularly PTH expression-that contribute to the increased risk of fracture and decreased fracture healing. Given the perturbations in PTH expression and the establishment of hPTH (1-34) for use in age-related osteoporosis, it was determined logical to attempt to ameliorate the bone phenotype found in T2DM using hPTH (1-34). Therefore, the present study had two aims: (i) to establish a suitable murine model of the skeletal fragility present in T2DM because no current consensus model exists; and (ii) to determine the effects of hPTH (1-34) on bone fractures in T2DM. The results of the present study suggest that the polygenic mouse of T2DM, TALLYHO/JngJ, most accurately recapitulates the diabetic osteoporotic phenotype seen in humans and that the intermittent systemic administration of hPTH (1-34) increases fracture healing in T2DM murine models by increasing the proliferation of mesenchymal stem cells. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Kareme D Alder
- Department of Orthopædics & RehabilitationYale University, School of MedicineNew HavenCTUSA
| | - Andrew HA White
- Department of Orthopædics & RehabilitationYale University, School of MedicineNew HavenCTUSA
| | - Yeon‐Ho Chung
- Department of Orthopædics & RehabilitationYale University, School of MedicineNew HavenCTUSA
| | - Inkyu Lee
- Department of Orthopædics & RehabilitationYale University, School of MedicineNew HavenCTUSA
- Department of Life ScienceChung‐Ang UniversitySeoulRepublic of Korea
| | - JungHo Back
- Department of Orthopædics & RehabilitationYale University, School of MedicineNew HavenCTUSA
| | - Hyuk‐Kwon Kwon
- Department of Orthopædics & RehabilitationYale University, School of MedicineNew HavenCTUSA
| | - Sean V Cahill
- Department of Orthopædics & RehabilitationYale University, School of MedicineNew HavenCTUSA
| | - Zichen Hao
- Department of Orthopædics & RehabilitationYale University, School of MedicineNew HavenCTUSA
| | - Lu Li
- Department of Orthopædics & RehabilitationYale University, School of MedicineNew HavenCTUSA
| | - Fancheng Chen
- Department of Orthopædics & RehabilitationYale University, School of MedicineNew HavenCTUSA
| | - Saelim Lee
- Department of Orthopædics & RehabilitationYale University, School of MedicineNew HavenCTUSA
| | - Matthew D Riedel
- Department of Orthopædics & RehabilitationYale University, School of MedicineNew HavenCTUSA
| | - Francis Y Lee
- Department of Orthopædics & RehabilitationYale University, School of MedicineNew HavenCTUSA
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Ramenzoni LL, Bösch A, Proksch S, Attin T, Schmidlin PR. Effect of high glucose levels and lipopolysaccharides-induced inflammation on osteoblast mineralization over sandblasted/acid-etched titanium surface. Clin Implant Dent Relat Res 2020; 22:213-219. [PMID: 32026615 DOI: 10.1111/cid.12884] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 12/02/2019] [Accepted: 01/16/2020] [Indexed: 11/28/2022]
Abstract
BACKGROUND AND PURPOSE Poorly controlled diabetes mellitus has been related to higher risk of implant treatment complications due to increased susceptibility to infection and delayed wound healing. Lipopolysaccharides (LPS) stimulate cytokine production leading to chronic inflammation and immunological host response that accentuates the destruction of periodontal tissues. This study aimed to evaluate the effect of different glycemic conditions on secretion and mineralization of bone matrix under sterile inflammation induced by LPS on osteoblasts seeded over sandblasted/acid-etched (SLA) titanium surface. MATERIALS AND METHODS Osteoblast cell viability was performed to determine the influence of different glucose concentrations (5.5, 8, 12, and 24 mM), which were chosen to reflect normal, postprandial, and high glucose values, similar to those typically seen in Diabetes mellitus under clinical conditions. Cells were seeded on titanium SLA discs (Straumann AG, Waldenburg, Switzerland) and exposed to glucose concentrations and LPS (1μg/mL) in order to test inflammatory response (qPCR) and mineralization (Alizarin Red staining). RESULTS Osteoblast viability was severely decreased when exposed to higher glucose levels (≥12 mM) and LPS (P < .05) compared to control. When the osteoblasts were exposed to LPS and glucose at ≥8 mM, the gene transcripts of inflammatory cytokines were ≈2.5-fold upregulated, while ≤8 mM glucose elicited no significant change compared to control without glucose treatment (P > .05). Osteoblasts exposed to LPS produced sparse extracellular matrix mineralization, especially combined with higher glucose values (≥12 mM), together with decreased calcium deposition compared to control (P < .05). CONCLUSIONS High glucose levels combined with LPS inflammatory stimulation elicited an adverse effect on the volume and quality of mineralized hard tissue formation on SLA titanium surfaces in vitro. Hence, both normal glucose levels and infection control including low levels of circulating LPS during initial osseointegration period may be required to increase the success rate of dental implants.
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Affiliation(s)
- Liza L Ramenzoni
- Clinic of Conservative and Preventive Dentistry, Center of Dental Medicine, University of Zurich, Zurich, Switzerland.,Laboratory of Applied Periodontal and Peri-implantitis Sciences, Clinic of Conservative and Preventive Dentistry, Center of Dental Medicine, University of Zurich, Zurich, Switzerland
| | - Adrian Bösch
- Clinic for Fixed and Removable Prosthodontics and Dental Material Science, University of Zurich, Zurich, Switzerland
| | - Susanne Proksch
- G.E.R.N. Tissue Replacement, Regeneration & Neogenesis, Department of Operative Dentistry and Periodontology, Medical Center, University of Freiburg, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
| | - Thomas Attin
- Laboratory of Applied Periodontal and Peri-implantitis Sciences, Clinic of Conservative and Preventive Dentistry, Center of Dental Medicine, University of Zurich, Zurich, Switzerland
| | - Patrick R Schmidlin
- Clinic of Conservative and Preventive Dentistry, Center of Dental Medicine, University of Zurich, Zurich, Switzerland.,Laboratory of Applied Periodontal and Peri-implantitis Sciences, Clinic of Conservative and Preventive Dentistry, Center of Dental Medicine, University of Zurich, Zurich, Switzerland
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Akyol S, Karagoz Z, Dingil Inan N, Butun I, Benli I, Demircan K, Yigitoglu MR, Akyol O, Sahin S, Ozyurt H. The gene expression and protein profiles of ADAMTS and TIMP in human chondrosarcoma cell lines induced by insulin: The potential mechanisms for skeletal and articular abnormalities in diabetes. ELECTRONIC JOURNAL OF GENERAL MEDICINE 2020. [DOI: 10.29333/ejgm/112767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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10
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Wang Z, Tang J, Li Y, Wang Y, Guo Y, Tu Q, Chen J, Wang C. AdipoRon promotes diabetic fracture repair through endochondral ossification-based bone repair by enhancing survival and differentiation of chondrocytes. Exp Cell Res 2019; 387:111757. [PMID: 31838062 DOI: 10.1016/j.yexcr.2019.111757] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 12/03/2019] [Accepted: 12/04/2019] [Indexed: 12/27/2022]
Abstract
Diabetic bone defects may exhibit impaired endochondral ossification (ECO) leading to delayed bone repair. AdipoRon, a receptor agonist of adiponectin polymers, can ameliorate diabetes and related complications, as well as overcome the disadvantages of the unstable structure of artificial adiponectin polymers. Here, the effects of AdipoRon on the survival and differentiation of chondrocytes in a diabetic environment were explored focusing on related mechanisms in gene and protein levels. In vivo, AdipoRon was applied to diet-induced-obesity (DIO) mice, a model of obesity and type 2 diabetes, with femoral fracture. Sequential histological evaluations and micro-CT were examined for further verification. We found that AdipoRon could ameliorate cell viability, apoptosis, and reactive oxygen species (ROS) production and promote mRNA expression of chondrogenic markers and cartilaginous matrix production of ATDC5 cells in high glucose medium via activating ERK1/2 pathway. Additionally, DIO mice with intragastric AdipoRon administration had more neocartilage and accelerated new bone formation. These data suggest that AdipoRon could stimulate bone regeneration via ECO in diabetes.
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Affiliation(s)
- Zhongyi Wang
- Jiangsu Key Laboratory of Oral Diseases, Department of Prosthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, 210029, China
| | - Jinxin Tang
- Jiangsu Key Laboratory of Oral Diseases, Department of Prosthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, 210029, China
| | - Ying Li
- Department of Stomatology, Jinan Central Hospital Affiliated to Shandong University, Jinan, 250013, China
| | - Yu Wang
- Jiangsu Key Laboratory of Oral Diseases, Department of Prosthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, 210029, China
| | - Yanyang Guo
- Jiangsu Key Laboratory of Oral Diseases, Department of Prosthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, 210029, China
| | - Qisheng Tu
- Tufts School of Dental Medicine, Sackler School of Graduate Biomedical Sciences, Tufts School of Medicine, Boston, 02111, USA
| | - Jake Chen
- Tufts School of Dental Medicine, Sackler School of Graduate Biomedical Sciences, Tufts School of Medicine, Boston, 02111, USA.
| | - Chen Wang
- Jiangsu Key Laboratory of Oral Diseases, Department of Prosthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, 210029, China.
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11
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Mohsin S, Kaimala S, AlTamimi EKY, Tariq S, Adeghate E. In vivo Labeling of Bone Microdamage in an Animal Model of Type 1 Diabetes Mellitus. Sci Rep 2019; 9:16994. [PMID: 31740777 PMCID: PMC6861243 DOI: 10.1038/s41598-019-53487-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Accepted: 10/21/2019] [Indexed: 01/23/2023] Open
Abstract
Type 1 diabetes mellitus (DM1) is linked to a decrease in bone strength. Bone strength entails both bone mineral density and bone quality. Limited data are available regarding diabetes-induced microdamage, which can severely influence bone quality. This study has investigated bone microdamage as a measure of bone quality in an animal model of DM1. Microdamage in the neck of the femur was labelled in vivo using multiple fluorochromes at 4, 12 and 24 weeks after the onset of DM1. Microcracks were quantified and their morphology analyzed using microscopy techniques. The mean length of microcracks at 24 weeks, and crack numerical and surface densities were significantly higher (p < 0.05) 4 weeks after the onset of DM1 when compared with control. Diffuse damage density was highest at 12 weeks after the onset of DM1. The arrangement of the collagen fibrils became progressively more irregular from 4 to 24 weeks of DM. This is the first study to analyze microdamage in vivo at different time points of DM1. DM1is associated with microcracks from the early stage, however bone microstructure shows toughening mechanisms that arrest their growth but disease progression further deteriorates bone quality resulting in longer microcracks which may increase fracture risk.
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Affiliation(s)
- Sahar Mohsin
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, PO Box. 17666, UAE.
| | - Suneesh Kaimala
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, PO Box. 17666, UAE
| | - Eman Khamis Yousef AlTamimi
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, PO Box. 17666, UAE
| | - Saeed Tariq
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, PO Box. 17666, UAE
| | - Ernest Adeghate
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, PO Box. 17666, UAE
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12
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Murray CE, Coleman CM. Impact of Diabetes Mellitus on Bone Health. Int J Mol Sci 2019; 20:ijms20194873. [PMID: 31575077 PMCID: PMC6801685 DOI: 10.3390/ijms20194873] [Citation(s) in RCA: 120] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 09/26/2019] [Accepted: 09/27/2019] [Indexed: 12/21/2022] Open
Abstract
Long-term exposure to a diabetic environment leads to changes in bone metabolism and impaired bone micro-architecture through a variety of mechanisms on molecular and structural levels. These changes predispose the bone to an increased fracture risk and impaired osseus healing. In a clinical practice, adequate control of diabetes mellitus is essential for preventing detrimental effects on bone health. Alternative fracture risk assessment tools may be needed to accurately determine fracture risk in patients living with diabetes mellitus. Currently, there is no conclusive model explaining the mechanism of action of diabetes mellitus on bone health, particularly in view of progenitor cells. In this review, the best available literature on the impact of diabetes mellitus on bone health in vitro and in vivo is summarised with an emphasis on future translational research opportunities in this field.
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Affiliation(s)
- Cliodhna E Murray
- Regenerative Medicine Institute, National University of Ireland, Galway, Biomedical Sciences Building, Dangan, Newcastle Road, Galway City, County Galway, H91W2TY, Ireland.
| | - Cynthia M Coleman
- Regenerative Medicine Institute, National University of Ireland, Galway, Biomedical Sciences Building, Dangan, Newcastle Road, Galway City, County Galway, H91W2TY, Ireland.
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Lau S, Lee M. Hyperglycaemia is an under-appreciated but modifiable risk factor in managing people with type 1 diabetes and fragility fractures. Foot (Edinb) 2019; 40:43-45. [PMID: 31082672 DOI: 10.1016/j.foot.2019.04.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 04/09/2019] [Accepted: 04/12/2019] [Indexed: 02/04/2023]
Abstract
There are two major musculoskeletal effects of Type 1 diabetes mellitus (T1DM) - fragility fractures and impaired fracture union. Fractures in these patients are a significant and limb threatening injury. Traditionally, they have been treated with prolonged immobilisation and as rigid as possible internal fixation. Recently, hyperglycaemia has been recognised as the most significant modifiable risk factor in treating patients with T1DM and fractured limbs. This article reviews this association further and outlines the role of orthopaedic surgeons in minimising orthopaedic-related complications.
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Affiliation(s)
- Simon Lau
- Royal Melbourne Hospital, Victoria, Australia.
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Lu Y, Alharbi M, Zhang C, O'Connor JP, Graves DT. Deletion of FOXO1 in chondrocytes rescues the effect of diabetes on mechanical strength in fracture healing. Bone 2019; 123:159-167. [PMID: 30904630 PMCID: PMC6491266 DOI: 10.1016/j.bone.2019.03.026] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 03/05/2019] [Accepted: 03/19/2019] [Indexed: 10/27/2022]
Abstract
Diabetes increases the risk of fracture, impairs fracture healing and causes rapid loss of the fracture callus cartilage, which was linked to increased FOXO1 expression in chondrocytes. We recently demonstrated that deletion of FOXO1 in chondrocytes blocked the premature removal of cartilage associated with endochondral bone formation during fracture healing. However, the ultimate impact of this deletion on mechanical strength was not investigated and remains unknown. Closed fractures were induced in Col2α1Cre+.FOXO1L/L mice with lineage specific deletion of FOXO1 in chondrocytes compared to littermate controls. Type 1 diabetes was induced by multiple low dose streptozotocin treatment. Thirty-five days after fracture micro CT analysis showed that diabetes significantly reduced callus volume and bone volume (P < 0.05), both which were reversed by FOXO1 deletion in chondrocytes. Diabetes significantly reduced mechanical strength measured by maximum torque, stiffness, modulus of rigidity and toughness and FOXO1 deletion in diabetic mice rescued each parameter (P < 0.05). Diabetes also reduced both bone volume and mechanical strength in non-fractured femurs. However, FOXO1 deletion did not affect bone volume or strength in non-fractured bone. These results point to the important effect that diabetes has on chondrocytes and show for the first time that the premature removal of cartilage induced by FOXO1 in chondrocytes has a significant impact on the mechanical strength of the healing bone.
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Affiliation(s)
- Yongjian Lu
- Department of Stomatology, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China; Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Mohammed Alharbi
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Endodontics, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Citong Zhang
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Implantology, School of Stomatology, Jilin University, Changchun 130021, China
| | - J Patrick O'Connor
- Department of Orthopaedics, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA
| | - Dana T Graves
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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Hung J, Al-Nakkash L, Broderick TL, Castro M, Plochocki JH. Leptin-deficient mice have altered three-dimensional growth plate histomorphometry. Diabetol Metab Syndr 2019; 11:8. [PMID: 30697359 PMCID: PMC6346570 DOI: 10.1186/s13098-019-0402-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 01/17/2019] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Leptin is an adipokine that regulates energy homeostasis and is also needed for normal bone growth and maintenance. Mutation in the lep gene, which characterizes the ob/ob mouse model, results in the development of obesity and type 2 diabetes mellitus, as well as reduced limb bone length and increased fracture risk. However, the relationship between limb bone length and growth plate cartilage structure in obese diabetic adolescents is incompletely understood. Here, we tested the hypothesis that leptin deficiency affects the microstructure of growth plate cartilage in juvenile ob/ob mice. METHODS Tibial growth plate cartilage structure was compared between lean and obese, leptin-deficient (ob/ob) female mice aged 10 weeks. We used confocal laser scanning microscopy to assess 3D histological differences in Z stacks of growth plate cartilage at 0.2 µm intervals, 80-100 µm in depth. Histomorphometric comparisons were made between juvenile lean and ob/ob mice. RESULTS We found obese mice have significantly reduced tibial length and growth plate height in comparison with lean mice (P < 0.05). Obese mice also have fewer chondrocyte columns in growth plate cartilage with reduced chondrocyte cell volumes relative to lean mice (P < 0.05). CONCLUSIONS These data help explicate the relationship between growth plate cartilage structure and bone health in obese diabetic juvenile mice. Our findings suggest obesity and diabetes may adversely affect growth plate cartilage structure.
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Affiliation(s)
- Jun Hung
- Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ 85308 USA
| | - Layla Al-Nakkash
- Department of Physiology, Midwestern University, Glendale, AZ 85308 USA
| | - Tom L. Broderick
- Department of Physiology, Midwestern University, Glendale, AZ 85308 USA
- Laboratory of Diabetes and Exercise Metabolism, Midwestern University, Glendale, AZ 85308 USA
| | - Monica Castro
- Department of Anatomy, Midwestern University, Glendale, AZ 85308 USA
| | - Jeffrey H. Plochocki
- Department of Anatomy, Midwestern University, Glendale, AZ 85308 USA
- Department of Medical Education, University of Central Florida College of Medicine, 6850 Lake Nona Blvd, Orlando, FL 32827 USA
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Metformin; an old antidiabetic drug with new potentials in bone disorders. Biomed Pharmacother 2018; 109:1593-1601. [PMID: 30551413 DOI: 10.1016/j.biopha.2018.11.032] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Revised: 11/05/2018] [Accepted: 11/07/2018] [Indexed: 01/15/2023] Open
Abstract
The prevalence of diabetes mellitus especially type 2 diabetes mellitus is increasing all over the world. In addition to cardiomyopathy and nephropathy, diabetics are at higher risk of mortality and morbidity due to greater risk of bone fractures and skeletal abnormalities. Patients with diabetes mellitus have lower bone quality in comparison to their non-diabetic counterparts mainly because of hyperglycemia, toxic effects of advanced glycosylation end-products (AGEs) on bone tissue, and impaired bone microvascular system. AGEs may also contribute to the development of osteoarthritis further to osteoporosis. Therefore, glycemic control in diabetic patients is vital for bone health. Metformin, a widely used antidiabetic drug, has been shown to improve bone quality and decrease the risk of fractures in patients with diabetes in addition to glycemic control and improving insulin sensitivity. AMP activated protein kinase (AMPK), the key molecule in metformin antidiabetic mechanism of action, is also effective in signaling pathways involved in bone physiology. This review, discusses the molecules linking diabetes and bone turnover, role of AMPK in bone metabolism, and the effect of metformin as an activator of AMPK on bone disorders and malignancies.
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What is the role of systemic conditions and options for manipulation of bone formation and bone resorption in rotator cuff tendon healing and repair? TECHNIQUES IN SHOULDER AND ELBOW SURGERY 2017; 18:113-120. [PMID: 28966557 DOI: 10.1097/bte.0000000000000121] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Rotator cuff pathology is a significant cause of shoulder pain. Operative repair of rotator cuff is an established standard of care for these patient, however, failure of the procedure is common. Systemic conditions such as diabetes mellitus, hypocholesteremia, thyroid disease, and smoking significantly affect the outcomes of rotator cuff repair and have significant implications for the management of these patients. Diabetes mellitus has been proposed to damage tendons through non-enzymatic glycosylation of collagen with advanced glycation end product formation and impaired microcirculation. Hypocholesteremia may lead to fatty infiltration and subsequent pro-inflammatory degenerative enzymatic degeneration. Thyroid disease may disrupt tendon homeostasis through the alteration of collagen production and the accumulation of glycosaminoglycans. Lastly, smoking inhibits tendon healing through the induction of hypovascularity and hypoperfusion. Understanding of the implications these systemic conditions have on the outcomes is important in the management of rotator cuff disease.
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Altered expression of SDF-1 and CXCR4 during fracture healing in diabetes mellitus. INTERNATIONAL ORTHOPAEDICS 2017; 41:1211-1217. [PMID: 28412763 DOI: 10.1007/s00264-017-3472-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 03/23/2017] [Indexed: 01/07/2023]
Abstract
PURPOSE Diabetes mellitus (DM) is known to impair fracture healing. The purpose of this study was to elucidate and compare the gene expression patterns and localization of stromal cell-derived factor 1 (SDF-1) and CXC chemokine receptor 4 (CXCR4) during fracture healing of the femur in rats with and without DM. METHODS Closed transverse fractures were created in the femurs of rats equally divided into a DM group and control group; DM was induced by streptozotocin. At post-fracture days five, seven, 11, 14, 21 and 28, total RNA was extracted from the fracture callus and mRNA expression levels of SDF-1 and CXCR4 were measured by real-time polymerase chain reaction. Localization of SDF-1 and CXCR4 proteins at the fracture site was determined by immunohistochemistry at days 21 and 28. RESULTS SDF-1 expression was significantly lower in the DM group than in the healthy group on days 21 and 28, and showed a significant difference between days 14 and 21 in the healthy group. There was no significant difference in CXCR4 expression levels between the healthy and DM groups at any time point. On day 21 immunoreactivity of SDF-1 and CXCR4 was detected at the fracture site of the healthy group but no immunoreactivity was observed in the DM group. On day 28, immunoreactivity of SDF-1 and CXCR4 was detected at the fracture site in both groups. CONCLUSION Gene expression and localization of SDF-1 and CXCR4 was altered during fracture healing, which may contribute to the impaired fracture healing in DM.
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Zhao Y, Hao J, Wang J, Wang J. Effect of Choline on the Composition and Degradation Enzyme of Extracellular Matrix of Mice Chondrocytes Exposed to Fluoride. Biol Trace Elem Res 2017; 175:414-420. [PMID: 27368532 DOI: 10.1007/s12011-016-0787-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 06/15/2016] [Indexed: 01/03/2023]
Abstract
Choline has been shown to mediate damage of the chondrocyte matrix and degradation enzymes of mice exposed to fluoride (F). To test the action of choline, pregnant mice were treated with differing amounts of F and choline. Newborn mice were weaned at 21 days after birth and treated with the same doses of F and choline as they mothers for 12 weeks. Using hematoxylin-eosin (HE) staining, real-time PCR (RT-PCR), and western blotting, changes in the structure of the cartilage, the expression of mRNA and protein related to proteoglycans (PG), and degradation enzymes were detected. The RT-PCR results show that the expression of the Aggrecan (Acan), transforming growth factor beta (TGF-β1), and Aggrecanases-1 gene were abnormal in the high fluoride (HiF) group, and treatments with choline reversed this phenomenon. The western blotting results show that the protein expression of Aggrecanases-1 was significantly increased in the HiF group (p < 0.01). These findings suggest that F can change the morphology of cartilage tissue, the gene expression of the Acan, TGF-β1, Aggrecanases-1, and the protein expression of the Acan, and that choline can attenuate the effect of F. This may provide the basis for the treatment and prevention of fluorosis.
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Affiliation(s)
- Yangfei Zhao
- Shanxi Key Laboratory of Environmental Veterinary Medicine, Shanxi Agricultural University, Taigu, Jinzhong, Shanxi, 030801, People's Republic of China
| | - Jing Hao
- Shanxi Key Laboratory of Environmental Veterinary Medicine, Shanxi Agricultural University, Taigu, Jinzhong, Shanxi, 030801, People's Republic of China
| | - Jinming Wang
- Shanxi Key Laboratory of Environmental Veterinary Medicine, Shanxi Agricultural University, Taigu, Jinzhong, Shanxi, 030801, People's Republic of China
| | - Jundong Wang
- Shanxi Key Laboratory of Environmental Veterinary Medicine, Shanxi Agricultural University, Taigu, Jinzhong, Shanxi, 030801, People's Republic of China.
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Thevendran G, Shah K, Pinney SJ, Younger AS. Perceived risk factors for nonunion following foot and ankle arthrodesis. J Orthop Surg (Hong Kong) 2017; 25:2309499017692703. [PMID: 28219308 DOI: 10.1177/2309499017692703] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND A major complication of foot and ankle arthrodesis is nonunion, which occurs in approximately 12% of cases. Various factors influence a patient's risk for nonunion following foot and ankle arthrodesis. We surveyed international foot and ankle surgeons to determine (1) risk factors perceived most important for nonunion, (2) factors considered absolute contraindications for arthrodesis, and (3) differences among expert groups regarding perceived risk factors and their stratification. METHODS A questionnaire was e-mailed to members of a major foot and ankle journal editorial board and four foot and ankle society executive committees. The relative risk of 18 potential nonunion risk factors was rated from 1 to 10, using smoking 1 pack/day as a benchmark score of 5.00. RESULTS The response rate was 72% (100/139); 81% declared foot and ankle surgery encompasses >90% of their practice. The highest perceived risk factors ( p < 0.001) were smoking 2 packs/day (mean score 8.69), lack of fusion site stability (8.66), and poor local vascularity (7.66). The least important risk factors ( p < 0.001) were perceived to be age >60 years (mean score 2.54), rheumatoid arthritis (3.05), and osteoporosis (3.56). The most frequently cited absolute contraindications to arthrodesis surgery were local infection (46%), poor local vascularity (41%), and smoking (32%). CONCLUSION To improve arthrodesis outcomes, resource allocation and patient and surgeon education should focus on smoking, construct stability, and local vascularity. Development of an objective nonunion risk assessment tool to identify patients at risk for nonunion using these results could help maximize the efficiency of available resources.
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Affiliation(s)
| | - Kalpesh Shah
- 2 Golden Jubilee National Hospital, Clydebank, Scotland, United Kingdom
| | - Stephen J Pinney
- 3 San Francisco Orthopaedic Surgeons Medical Group, San Francisco, CA, USA
| | - Alastair Se Younger
- 4 Department of Orthopaedics, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
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The impact of diabetes on dental implant failure: a systematic review and meta-analysis. Int J Oral Maxillofac Surg 2016; 45:1237-45. [DOI: 10.1016/j.ijom.2016.05.019] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2015] [Revised: 05/08/2016] [Accepted: 05/26/2016] [Indexed: 01/08/2023]
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Wang C, Yu T, Tan L, Cheng J. Bioinformatics analysis of gene expression profile in callus tissues of osteoporotic phenotype mice induced by osteoblast-specific Krm2 overexpression. Int J Rheum Dis 2016; 19:1263-1271. [PMID: 26929007 DOI: 10.1111/1756-185x.12840] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE The aim of this study was to explore the molecular mechanism of fracture healing in osteoporotic mice. METHODS The gene expression profiles of callus tissues of osteoporotic mice and controls were obtained from Gene Expression Omnibus database. The differentially expressed genes (DEGs) and their related biological function and pathways were investigated. In addition, the protein-protein interaction (PPI) network was constructed for DEG encoding proteins and the differentially expressed transcriptional factor was screened. RESULTS There were 275 up-regulated genes and 347 down-regulated genes. The collagen metabolic process biological function was significantly enriched by down-regulated genes. Extracellular matrix (ECM)-receptor interaction was a significant pathway that was enriched by differentially expressed genes. In PPI (protein-protein interaction) network, Pcna was the significant node with highest connective degrees. Other hub nodes, such as Ccnb2 and Rrm2, were closely associated with the p53 signaling pathway. Tal1 and Smad6 were found to be differentially expressed transcription factors. CONCLUSION The dysregulated collagen metabolic process, ECM-receptor interaction and p53 signaling pathway may be responsible for impaired fracture healing of osteoporotic mice. The hub nodes (such as Ccnb2 and Rrm2) and differentially expressed TFs (such as Tal1 and Smad6) play a critical role in bone remodeling of osteoporotic individuals.
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Affiliation(s)
- Chengxue Wang
- Department of Trauma, The First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Tiecheng Yu
- Department of Trauma, The First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Lei Tan
- Department of Trauma, The First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Jieping Cheng
- Department of Orthopaedics, The Second Hospital of Jilin University, Changchun, Jilin Province, China
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Affiliation(s)
- Maya S. Indurkar
- Department of Periodontology, Government Dental College & Hospital, Aurangabad, Maharashtra, India
| | - Arati S. Maurya
- Department of Periodontology, Government Dental College & Hospital, Aurangabad, Maharashtra, India
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Al-Hariri M. Sweet Bones: The Pathogenesis of Bone Alteration in Diabetes. J Diabetes Res 2016; 2016:6969040. [PMID: 27777961 PMCID: PMC5061963 DOI: 10.1155/2016/6969040] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2016] [Accepted: 09/15/2016] [Indexed: 01/22/2023] Open
Abstract
Diabetic patients have increased fracture risk. The pathogenesis underlying the status of bone alterations in diabetes mellitus is not completely understood but is multifactorial. The major deficits appear to be related to a deficit in mineralized surface area, a decrement in the rate of mineral apposition, deceased osteoid surface, depressed osteoblast activity, and decreased numbers of osteoclasts due to abnormal insulin signaling pathway. Other prominent features of diabetes mellitus are an increased urinary excretion of calcium and magnesium, accumulation of advanced glycation end products, and oxidative stress leading to sweet bones (altered bone's strength, metabolism, and structure). Every diabetic patient should be assessed for risk factors for fractures and osteoporosis. The pathogenesis of the bone alterations in diabetes mellitus as well as their molecular mechanisms needs further study.
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Affiliation(s)
- Mohammed Al-Hariri
- Department of Physiology, College of Medicine, University of Dammam, P. O. Box 2114-31451, Dammam, Saudi Arabia
- *Mohammed Al-Hariri:
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Conte A, Ghiraldini B, Casarin R, Casati M, Pimentel S, Cirano F, Duarte P, Ribeiro F. Impact of type 2 diabetes on the gene expression of bone-related factors at sites receiving dental implants. Int J Oral Maxillofac Surg 2015; 44:1302-8. [DOI: 10.1016/j.ijom.2015.06.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Revised: 05/29/2015] [Accepted: 06/01/2015] [Indexed: 12/11/2022]
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Thevendran G, Wang C, Pinney SJ, Penner MJ, Wing KJ, Younger ASE. Nonunion Risk Assessment in Foot and Ankle Surgery: Proposing a Predictive Risk Assessment Model. Foot Ankle Int 2015; 36:901-7. [PMID: 25810460 DOI: 10.1177/1071100715577789] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND Nonunion risk factor identification and modification are subjective. We describe and validate a predictive nonunion risk factor model to identify foot and ankle operative patients at risk for nonunion. MATERIALS AND METHODS One hundred international experts in foot and ankle surgery were surveyed. Nineteen nonunion risk factors were stratified into 3 categories: more significant than, as significant as, and less significant than smoking 1 pack per day. A nonunion risk assessment model was developed by assigning a weighted score to each risk factor, based on its mean score from the survey. A total nonunion risk (TNR) score was calculated for individual patients. It was retrospectively validated in 2 patient cohorts from a single center's prospectively collected end-stage ankle arthritis patient database: 22 cases of ankle and/or hindfoot fusion nonunion and 40 sex- and procedure-matched controls with bony fusion. Analyses included descriptive statistics, logistic regression, and univariate and multivariate linear regression models. RESULTS The mean TNR score was 6.6 ± 5.6 in controls and 13.5 ± 8.2 in the nonunion group (P < .001). Data showed excellent intraobserver and interobserver correlation coefficients. In a logistic regression model, the risk of nonunion exceeded 9% with a TNR score greater than or equal to 10. Multivariate linear regression analysis, adjusted for age and sex, suggested that lack of fusion site stability and obesity (body mass index greater than 30) were significantly predictive of nonunion. CONCLUSION The nonunion risk assessment model provides a reliable, sensitive, and specific method for predicting nonunion based on objective patient assessment. Orthopaedic patients at risk for nonunion could benefit from targeted intervention. LEVEL OF EVIDENCE Level IV, retrospective observational study.
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Affiliation(s)
| | - Calvin Wang
- Abbotsford Regional Hospital and Cancer Centre, Abbotsford, British Columbia, Canada
| | - Stephen J Pinney
- San Francisco Orthopaedic Surgeons Medical Group, San Francisco, CA, USA
| | - Murray J Penner
- Division of Distal Extremities, Department of Orthopaedics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Kevin J Wing
- Division of Distal Extremities, Department of Orthopaedics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Alastair S E Younger
- Division of Distal Extremities, Department of Orthopaedics, University of British Columbia, Vancouver, British Columbia, Canada British Columbia's Foot and Ankle Clinic, St Paul's Hospital, Vancouver, British Columbia, Canada
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Khan MP, Singh AK, Joharapurkar AA, Yadav M, Shree S, Kumar H, Gurjar A, Mishra JS, Tiwari MC, Nagar GK, Kumar S, Ramachandran R, Sharan A, Jain MR, Trivedi AK, Maurya R, Godbole MM, Gayen JR, Sanyal S, Chattopadhyay N. Pathophysiological Mechanism of Bone Loss in Type 2 Diabetes Involves Inverse Regulation of Osteoblast Function by PGC-1α and Skeletal Muscle Atrogenes: AdipoR1 as a Potential Target for Reversing Diabetes-Induced Osteopenia. Diabetes 2015; 64:2609-23. [PMID: 25633418 DOI: 10.2337/db14-1611] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 01/26/2015] [Indexed: 11/13/2022]
Abstract
Type 2 diabetes is associated with increased fracture risk and delayed fracture healing; the underlying mechanism, however, remains poorly understood. We systematically investigated skeletal pathology in leptin receptor-deficient diabetic mice on a C57BLKS background (db). Compared with wild type (wt), db mice displayed reduced peak bone mass and age-related trabecular and cortical bone loss. Poor skeletal outcome in db mice contributed high-glucose- and nonesterified fatty acid-induced osteoblast apoptosis that was associated with peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) downregulation and upregulation of skeletal muscle atrogenes in osteoblasts. Osteoblast depletion of the atrogene muscle ring finger protein-1 (MuRF1) protected against gluco- and lipotoxicity-induced apoptosis. Osteoblast-specific PGC-1α upregulation by 6-C-β-d-glucopyranosyl-(2S,3S)-(+)-5,7,3',4'-tetrahydroxydihydroflavonol (GTDF), an adiponectin receptor 1 (AdipoR1) agonist, as well as metformin in db mice that lacked AdipoR1 expression in muscle but not bone restored osteopenia to wt levels without improving diabetes. Both GTDF and metformin protected against gluco- and lipotoxicity-induced osteoblast apoptosis, and depletion of PGC-1α abolished this protection. Although AdipoR1 but not AdipoR2 depletion abolished protection by GTDF, metformin action was not blocked by AdipoR depletion. We conclude that PGC-1α upregulation in osteoblasts could reverse type 2 diabetes-associated deterioration in skeletal health.
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Affiliation(s)
- Mohd Parvez Khan
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
| | - Abhishek Kumar Singh
- Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
| | | | - Manisha Yadav
- Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
| | - Sonal Shree
- Division of Molecular and Structural Biology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
| | - Harish Kumar
- Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
| | - Anagha Gurjar
- Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
| | - Jay Sharan Mishra
- Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
| | - Mahesh Chandra Tiwari
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
| | - Geet Kumar Nagar
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
| | - Sudhir Kumar
- Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
| | - Ravishankar Ramachandran
- Division of Molecular and Structural Biology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
| | - Anupam Sharan
- Vinayak Cosmetic Surgery & Laser Centre, Lucknow, Uttar Pradesh, India
| | | | - Arun Kumar Trivedi
- Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
| | - Rakesh Maurya
- Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
| | - Madan Madhav Godbole
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Jiaur Rahaman Gayen
- Division of Pharmacokinetics and Metabolism, CSIR-Central Drug Research Institute, Lucknow, UP, India
| | - Sabyasachi Sanyal
- Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
| | - Naibedya Chattopadhyay
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
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Oates TW, Galloway P, Alexander P, Vargas Green A, Huynh-Ba G, Feine J, McMahan CA. The effects of elevated hemoglobin A(1c) in patients with type 2 diabetes mellitus on dental implants: Survival and stability at one year. J Am Dent Assoc 2014; 145:1218-26. [PMID: 25429035 PMCID: PMC4403726 DOI: 10.14219/jada.2014.93] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND The authors conducted a prospective cohort study to determine whether poor glycemic control is a contraindication to implant therapy in patients with type 2 diabetes. METHODS The study sample consisted of 117 edentulous patients, each of whom received two mandibular implants, for a total of 234 implants. Implant-retained mandibular overdentures were loaded after a four-month healing period and followed up for an additional one year. The authors assessed implant survival and stability (by means of resonance frequency analysis) relative to glycated hemoglobin A1c (HbA1c) levels, with baseline levels up to 11.1 percent and levels as high as 13.3 percent over one year. RESULTS Implant survival rates for 110 of 117 patients who were followed up for one year after loading were 99.0 percent, 98.9 percent and 100 percent, respectively, for patients who did not have diabetes (n = 47), those with well-controlled diabetes (n = 44) and those with poorly controlled diabetes (n = 19). The authors considered the seven patients lost to follow-up as having had failed implants; consequently, their conservative estimates of survival rates in the three groups were 93.0 percent, 92.6 percent and 95.0 percent (P = .6510). Two implants failed at four weeks, one in the nondiabetes group and the other in the well-controlled diabetes group. Delays in implant stabilization were related directly to poor glycemic control. CONCLUSIONS The results of this study indicate that elevated HbA1c levels in patients with type 2 diabetes were not associated with altered implant survival one year after loading. However, alterations in early bone healing and implant stability were associated with hyperglycemia.
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Affiliation(s)
- Thomas W Oates
- Dr. Oates is a professor, Department of Periodontics, School of Dentistry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MCS 7888, San Antonio, Texas 78229-3900, e-mail . Address correspondence to Dr. Oates
| | - Patrick Galloway
- Dr. Galloway is a former resident, Department of Periodontics, School of Dentistry, University of Texas Health Science Center at San Antonio
| | - Peggy Alexander
- Dr. Alexander is a clinical professor, Department of Periodontics, School of Dentistry, University of Texas Health Science Center at San Antonio
| | - Adriana Vargas Green
- Dr. Vargas Green is an associate professor, Department of Comprehensive Dentistry, School of Dentistry, University of Texas Health Science Center at San Antonio
| | - Guy Huynh-Ba
- Dr. Huynh-Ba is an associate professor, Department of Periodontics, School of Dentistry, University of Texas Health Science Center at San Antonio
| | - Jocelyn Feine
- Dr. Feine is a professor, Oral Health and Society Research Unit, Faculty of Dentistry, McGill University, Montreal, Quebec, Canada
| | - C Alex McMahan
- Dr. McMahan is a professor, Department of Pathology, University of Texas Health Science Center at San Antonio
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Liporace FA, Breitbart EA, Yoon RS, Doyle E, Paglia DN, Lin S. The effect of locally delivered recombinant human bone morphogenetic protein-2 with hydroxyapatite/tri-calcium phosphate on the biomechanical properties of bone in diabetes-related osteoporosis. J Orthop Traumatol 2014; 16:151-9. [PMID: 25421865 PMCID: PMC4441641 DOI: 10.1007/s10195-014-0327-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Accepted: 11/07/2014] [Indexed: 01/05/2023] Open
Abstract
Background Recombinant human bone morphogenetic protein-2 (rhBMP-2) is particularly effective in improving osteogenesis in patients with diminished bone healing capabilities, such as individuals with type 1 diabetes mellitus (T1DM) who have impaired bone healing capabilities and increased risk of developing osteoporosis. This study measured the effects of rhBMP-2 treatment on osteogenesis by observing the dose-dependent effect of localized delivery of rhBMP-2 on biomechanical parameters of bone using a hydroxyapatite/tri-calcium phosphate (HA/TCP) carrier in a T1DM-related osteoporosis animal model. Materials and methods Two different doses of rhBMP-2 (LD low dose, HD high dose) with a HA/TCP carrier were injected into the femoral intramedullary canal of rats with T1DM-related osteoporosis. Two more diabetic rat groups were injected with saline alone and with HA/TCP carrier alone. Radiographs and micro-computed tomography were utilized for qualitative assessment of bone mineral density (BMD). Biomechanical testing occurred at 4- and 8-week time points; parameters tested included torque to failure, torsional rigidity, shear stress, and shear modulus. Results At the 4-week time point, the LD and HD groups both exhibited significantly higher BMD than controls; at the 8-week time point, the HD group exhibited significantly higher BMD than controls. Biomechanical testing revealed dose-dependent, higher trends in all parameters tested at the 4- and 8-week time points, with minimal significant differences. Conclusions Groups treated with rhBMP-2 demonstrated improved bone mineral density at both 4 and 8 weeks compared to control saline groups, in addition to strong trends towards improvement of intrinsic and extrinsic biomechanical properties when compared to control groups. Data revealed trends toward dose-dependent increases in peak torque, torsional rigidity, shear stress, and shear modulus 4 weeks after rhBMP-2 treatment. Level of evidence Not applicable.
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Affiliation(s)
- Frank A Liporace
- Division of Orthopaedic Trauma, Department of Orthopaedic Surgery, NYU Hospital for Joint Diseases, 301 E 17th Street, Suite 1402, New York, NY, 10003, USA,
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Dubey RK, Gupta DK, Singh AK. Dental implant survival in diabetic patients; review and recommendations. Natl J Maxillofac Surg 2014; 4:142-50. [PMID: 24665167 PMCID: PMC3961886 DOI: 10.4103/0975-5950.127642] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Rising population of diabetic individuals across the world has become a big concern to the society. The persistent hyperglycemia may affect each and every tissue and consequently results in morbidity and eventually mortality in diabetic patients. A direct negative response of diabetes has been observed on oral tissues with few contradictions however, little are known about effect of diabetes on dental implant treatment and the consequent results. Many studies concerned with osteointegration and prognosis of dental implant in diabetic patients have been conducted and published since 1994. These studies have been critically reviewed to understand the impact of diabetes on the success of dental implant and the factors to improve osseointegration and consequently survival of dental implant in diabetic patients. Theoretical literatures and studies in diabetic animals substantiate high failure rate of implants but most of clinical studies indicated statistically insignificant failure of dental implants even in moderately uncontrolled diabetic patients. Success of dental implant in well and fairly controlled diabetic patients with proper treatment planning, prophylactic remedies and adequate postsurgical maintenance appears as good as normal individuals.
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Affiliation(s)
- Rajendra Kumar Dubey
- Department of Prosthodontics, Government Dental College, Raipur, Chhattisgarh, India
| | - Deepesh Kumar Gupta
- Department of Prosthodontics, Government Dental College, Raipur, Chhattisgarh, India
| | - Amit Kumar Singh
- Department of Prosthodontics, PIDS, Gorakhpur, Uttar Pradesh, India
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Wolfson TS, Hamula MJ, Jazrawi LM. Impact of diabetes mellitus on surgical outcomes in sports medicine. PHYSICIAN SPORTSMED 2013; 41:64-77. [PMID: 24231598 DOI: 10.3810/psm.2013.11.2037] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Diabetes mellitus (DM) affects a significant proportion of the patients evaluated and treated by orthopedic surgeons who specialize in sports medicine. Sports-medicine-related conditions associated with DM include tendinopathy, adhesive capsulitis of the shoulder, and articular cartilage disease. This article reviews the current literature adressing the effect of DM on surgical outcomes in sports medicine. In general, patients with DM undergo operations more frequently and experience inferior surgical outcomes compared with patients without DM. Diabetes mellitus is associated with increased rates of complications from sports medicine procedures, such as infection, delayed healing, and failure of the operation. However, additional research is needed to determine the full impact of DM on patient outcomes in sports medicine. Surgeons should be cognizant of special considerations in the population of patients with DM and aim to tailor the surgical management of this growing patient population.
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Affiliation(s)
- Theodore S Wolfson
- Department of Orthopaedic Surgery, New York University Hospital for Joint Diseases, New York, NY
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Casazza K, Hanks LJ, Clines GA, Tse HM, Eberhardt AW. Diabetes-related impairment in bone strength is established early in the life course. World J Diabetes 2013; 4:145-150. [PMID: 23961325 PMCID: PMC3746087 DOI: 10.4239/wjd.v4.i4.145] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2013] [Revised: 04/24/2013] [Accepted: 06/19/2013] [Indexed: 02/05/2023] Open
Abstract
AIM: To evaluate properties of bone quantity/quality using young non-obese Type 1 (T1D)-diabetic (NOD) prone and syngenic non-diabetic (NOD.scid) mice.
METHODS: Quantitative bone assessment of tibia was conducted using dual-energy X-ray absorptiometry (DXA) for the evaluation of body mass, bone mineral content, body fat mass and lean mass. Qualitative assessment was accomplished by three-point breakage for assessment of force to failure and micro-computed tomography for evaluation of trabecular and cortical properties of bone. In addition, fasting blood was evaluated prior to sacrifice at week eleven and fifteen to evaluate and compare glucose homeostasis between the strains of mice.
RESULTS: Our findings support a perturbation in the relationship between bone quantity, quality, and subsequently, the association between structure and strength. There were no differences in DXA-assessed body composition (body fat, % fat mass and lean mass) and bone composition (bone mineral content and bone mineral density) between strains. However, relative to NOD.scid, NOD mice had lower trabecular bone volume, relative trabecular bone volume, trabecular number and trabecular total material density (P < 0.05). Conversely, NOD mice had greater cortical total mean volume (P < 0.05). General linear models analysis adjusted for body weight revealed a significant contribution of T1D to bone health as early as 5 wk.
CONCLUSION: It is well-established that diabetes is a significant risk factor for increased fractures, although the underlying mechanisms are not fully understood. Investigation of bone parameters encompassing strength and structure early in the life course will facilitate the elucidation of the pathogenesis of impaired bone integrity.
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Jolly SJ, Hegde C, Shetty NS. Assessment of Maxillary and Mandibular Bone Density in Controlled Type II Diabetes: A Computed Tomography Study. J ORAL IMPLANTOL 2013; 41:400-5. [PMID: 23834616 DOI: 10.1563/aaid-joi-d-12-00248] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
This study was undertaken to compare the bone density in nondiabetic and controlled type II diabetes patients using spiral computed tomography. A group of 40 edentulous men, comprising of 20 nondiabetics and 20 controlled type II diabetics between the ages of 50-65 years, were enrolled in the study. Glycemic control of the diabetic patients was assessed by glycosylated hemoglobin level. The controlled diabetic group had an HbA1c level between 6.1-8%. A radiographic stent was prepared by using chemically cured resin. Bone densities at trabecular, buccal, and lingual cortical regions of maxillary and mandibular edentulous arches were measured by a tomography machine. Mean bone density measurements were recorded in Hounsfield units. The data thus obtained from 10 sites of maxillary and mandibular arches were tabulated and analyzed using SPSS statistical software. This study showed no significant changes in bone density between the controlled diabetic and nondiabetic subjects. Within the limitation of this study, it can be concluded that bone density does not seem to be affected in controlled type II diabetics.
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Affiliation(s)
- Sanju John Jolly
- 1 Department of Prosthodontics, Indira Gandhi Institute of Dental Sciences, Nellikuzhi, Kothamangalam, Ernakulam District, Kerala State, India
| | - Chethan Hegde
- 2 Department of Prosthodontics, A.B. Shetty Memorial Institute of Dental Sciences, Deralakatte, Mangalore, Karnataka State, India
| | - N Sridhar Shetty
- 2 Department of Prosthodontics, A.B. Shetty Memorial Institute of Dental Sciences, Deralakatte, Mangalore, Karnataka State, India
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Köttstorfer J, Kaiser G, Thomas A, Gregori M, Kecht M, Domaszewski F, Sarahrudi K. The influence of non-osteogenic factors on the expression of M-CSF and VEGF during fracture healing. Injury 2013; 44:930-4. [PMID: 23570706 DOI: 10.1016/j.injury.2013.02.028] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2012] [Revised: 02/08/2013] [Accepted: 02/27/2013] [Indexed: 02/02/2023]
Abstract
INTRODUCTION Macrophage colony stimulating factor (M-CSF) as well as vascular endothelial growth factor (VEGF) play an important role in bone homeostasis and in the process of fracture healing. To date, limited data regarding the influence of age, gender, diabetes, smoking, and alcohol consumption on the systemic expression of M-CSF and VEGF after long bone fracture exist. METHODS From a total of 113 patients with long bone fractures 51 patients met inclusion criteria and were finally enrolled in this study. Patient's serum was collected over a period of 6 months following a standardised time schedule. M-CSF and VEGF serum concentrations were measured. Patient's history with special focus on cigarette smoking, diabetes mellitus, and regular alcohol intake was recorded. All patients were followed up clinically and radiologically for at least 24 weeks after trauma. A total of 22 male and 29 female patients formed the study population. RESULTS The present results show significantly elevated mean overall M-CSF serum concentration in women, older patients as well as in non-smoking individuals. The mean overall VEGF serum concentration was significantly higher in women, older patients, and diabetic individuals as well as in non-smokers. Statistically significant differences were not observed at any time point regarding alcohol consumption. CONCLUSION These results suggest that age, gender, diabetes mellitus and cigarette smoking significantly influence the expression of M-CSF and VEGF after fracture of long bones in human. Of note, diabetic patients showed significantly elevated overall VEGF levels when compared to non-diabetic patients. Therefore, further studies with larger patient cohorts are needed to better understand the influence of these endogenous and exogenous factors on the expression of the osteogenic during human fracture healing.
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Affiliation(s)
- J Köttstorfer
- Department of Trauma Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
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Paglia DN, Wey A, Breitbart EA, Faiwiszewski J, Mehta SK, Al-Zube L, Vaidya S, Cottrell JA, Graves D, Benevenia J, O’Connor JP, Lin SS. Effects of local insulin delivery on subperiosteal angiogenesis and mineralized tissue formation during fracture healing. J Orthop Res 2013; 31:783-91. [PMID: 23238777 PMCID: PMC6446235 DOI: 10.1002/jor.22288] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2012] [Accepted: 11/08/2012] [Indexed: 02/04/2023]
Abstract
Local insulin delivery has been shown to improve osseous healing in diabetic animals. The purpose of this study was to quantify the effects of local intramedullary delivery of saline or Ultralente insulin (UL) on various fracture healing parameters using an in vivo non-diabetic BB Wistar rat model. Quantitation of local insulin levels showed a rapid release of insulin from the fractured femora, demonstrating complete release at 2 days. RT-PCR analysis revealed that the expression of early osteogenic markers (Col1α2, osteopontin) was significantly enhanced with UL treatment when compared with saline controls (p < 0.05). Significant differences in VEGF + cells and vascularity were evident between the treatment and control groups at day 7 (p < 0.05). At day 21, histomorphometric analysis demonstrated a significant increase in percent mineralized tissue in the UL-treated animals compared with controls (p < 0.05), particularly within the subperiosteal region of the fracture callus. Mechanical testing at 4 weeks showed significantly greater mechanical strength for UL-treated animals (p < 0.05), but healing in control animals caught up at 6 weeks post-fracture. These results suggest that the primary osteogenic effect of UL during the early stages of fracture healing (1-3 weeks) is through an increase in osteogenic gene expression, subperiosteal angiogenesis, and mineralized tissue formation.
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Affiliation(s)
- David N. Paglia
- Department of Orthopaedics, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, 90 Bergen Street, Suite 7300, Newark, New Jersey 07103
| | - Aaron Wey
- Department of Orthopaedics, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, 90 Bergen Street, Suite 7300, Newark, New Jersey 07103
| | - Eric A. Breitbart
- Department of Orthopaedics, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, 90 Bergen Street, Suite 7300, Newark, New Jersey 07103
| | - Jonathan Faiwiszewski
- Department of Orthopaedics, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, 90 Bergen Street, Suite 7300, Newark, New Jersey 07103
| | - Siddhant K. Mehta
- Department of Orthopaedics, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, 90 Bergen Street, Suite 7300, Newark, New Jersey 07103
| | - Loay Al-Zube
- Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, Newark, New Jersey,Department of Biomedical Engineering, The Hashemite University, Zarqa 13115, Jordan
| | - Swaroopa Vaidya
- Department of Orthopaedics, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, 90 Bergen Street, Suite 7300, Newark, New Jersey 07103,Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, Newark, New Jersey
| | - Jessica A. Cottrell
- Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, Newark, New Jersey
| | - Dana Graves
- Department of Periodontics, University of Pennsylvania, 240 South 40 Street, Philadelphia, PA, 19104
| | - Joseph Benevenia
- Department of Orthopaedics, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, 90 Bergen Street, Suite 7300, Newark, New Jersey 07103
| | - J. Patrick O’Connor
- Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, Newark, New Jersey
| | - Sheldon S. Lin
- Department of Orthopaedics, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, 90 Bergen Street, Suite 7300, Newark, New Jersey 07103
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36
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Chang PC, Lim LP. Interrelationships of periodontitis and diabetes: A review of the current literature. J Dent Sci 2012. [DOI: 10.1016/j.jds.2012.02.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
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Oates TW, Huynh-Ba G, Vargas A, Alexander P, Feine J. A critical review of diabetes, glycemic control, and dental implant therapy. Clin Oral Implants Res 2011; 24:117-27. [PMID: 22111901 DOI: 10.1111/j.1600-0501.2011.02374.x] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/15/2011] [Indexed: 12/18/2022]
Abstract
OBJECTIVES To systematically examine the evidence guiding the use of implant therapy relative to glycemic control for patients with diabetes and to consider the potential for both implant therapy to support diabetes management and hyperglycemia to compromise implant integration. MATERIAL AND METHODS A systematic approach was used to identify and review clinical investigations directly assessing implant survival or failure for patients with diabetes. A MEDLINE (PubMED) database search identified potential articles for inclusion using the search strategy: (dental implants OR oral implants) AND (diabetes OR diabetic). Inclusion in this review required longitudinal assessments including at least 10 patients, with included articles assessed relative to documentation of glycemic status for patients. RESULTS Although the initial search identified 129 publications, this was reduced to 16, for inclusion. Reported implant failure rates for diabetic patients ranged from 0% to 14.3%. The identification and reporting of glycemic control was insufficient or lacking in 13 of the 16 studies with 11 of these enrolling only patients deemed as having acceptable glycemic control, limiting interpretation of findings relative to glycemic control. Three of the 16 studies having interpretable information on glycemic control failed to demonstrate a significant relationship between glycemic control and implant failure, with failure rates ranging from 0% to 2.9%. CONCLUSIONS Clinical evidence is lacking for the association of glycemic control with implant failure while support is emerging for implant therapy in diabetes patients with appropriate accommodations for delays in implant integration based on glycemic control. The role for implants to improve oral function in diabetes management and the effects of hyperglycemia on implant integration remain to be determined.
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Affiliation(s)
- Thomas W Oates
- Department of Periodontics, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA.
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Hou CJ, Liu JL, Li X, Bi LJ. Insulin promotes bone formation in augmented maxillary sinus in diabetic rabbits. Int J Oral Maxillofac Surg 2011; 41:400-7. [PMID: 22099315 DOI: 10.1016/j.ijom.2011.10.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2010] [Revised: 07/18/2011] [Accepted: 10/07/2011] [Indexed: 12/01/2022]
Abstract
The role of insulin during the formation of bone in the augmented space of the maxillary sinus in patients with diabetes is unclear. The authors compared the differences in bone formation after maxillary sinus floor elevation in diabetic and healthy animals and evaluated the effects of insulin on osteogenesis and the differentiation and activities of the osteoblasts. 10 male Japanese white rabbits were divided into two groups after diabetic induction by a single injection of monohydrated alloxan and having maintained steady blood glucose levels. The groups included the diabetes mellitus group (DM; n=5) and the DM+insulin group (n=5); another five healthy rabbits comprised the control group. Maxillary sinus floor elevation was performed by grafting hydroxyapatite particles. Compared with the control group, the newly formed bone area, number of blood vessels and osteoblasts, collagen I content and serum osteocalcin levels were significantly decreased in DM rabbits (P<0.01). Insulin treatment reversed the decrease in bone formation, blood vessels, osteoblasts, collagen I and serum osteocalcin (P<0.01). Insulin treatment also promoted osteogenesis in the augmented space of the diabetic rabbits, which might have resulted from promotion of osteoblast differentiation and upregulation of neovascularization.
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Affiliation(s)
- C-J Hou
- Department of Stomatology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
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Wu JC, Huang WC, Tsai HW, Ko CC, Wu CL, Tu TH, Cheng H. Pedicle screw loosening in dynamic stabilization: incidence, risk, and outcome in 126 patients. Neurosurg Focus 2011; 31:E9. [DOI: 10.3171/2011.7.focus11125] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Object
The long-term outcome of lumbar dynamic stabilization is uncertain. This study aimed to investigate the incidence, risk factors, and outcomes associated with screw loosening in a dynamic stabilization system.
Methods
The authors conducted a retrospective review of medical records, radiological studies, and clinical evaluations obtained in consecutive patients who underwent 1- or 2-level lumbar dynamic stabilization and were followed up for more than 24 months. Loosening of screws was determined on radiography and CT scanning. Radiographic and standardized clinical outcomes, including the visual analog scale (VAS) and Oswestry Disability Index (ODI) scores, were analyzed with a focus on cases in which screw loosening occurred.
Results
The authors analyzed 658 screws in 126 patients, including 54 women (42.9%) and 72 men (57.1%) (mean age 60.4 ± 11.8 years). During the mean clinical follow-up period of 37.0 ± 7.1 months, 31 screws (4.7%) in 25 patients (19.8%) were shown to have loosened. The mean age of patients with screw loosening was significantly higher than those without loosening (64.8 ± 8.8 vs 59.3 ± 12.2, respectively; p = 0.036). Patients with diabetes mellitus had a significantly higher rate of screw loosening compared with those without diabetes (36.0% vs 15.8%, respectively; p = 0.024). Diabetic patients with well-controlled serum glucose (HbA1c ≤ 8.0%) had a significantly lower chance of screw loosening than those without well-controlled serum glucose (28.6% vs 71.4%, respectively; p = 0.021). Of the 25 patients with screw loosening, 22 cases (88%) were identified within 6.6 months of surgery; 18 patients (72%) had the loosened screws in the inferior portion of the spinal construct, whereas 7 (28%) had screw loosening in the superior portion of the construct. The overall clinical outcomes at 3, 12, and 24 months, measured by VAS for back pain, VAS for leg pain, and ODI scores, were significantly improved after surgery compared with before surgery (all p < 0.05). There were no significant differences between the patients with and without screw loosening at all evaluation time points (all p > 0.05). All 25 patients with screw loosening were asymptomatic, and in 6 (24%) osseous integration was demonstrated on later follow-up. Also, there were 3 broken screws (2.38% in 126 patients or 0.46% in 658 screws). To date, none of these loosened or broken screws have required revision surgery.
Conclusions
Screw loosening in dynamic stabilization systems is not uncommon (4.7% screws in 19.8% patients). Patients of older age or those with diabetes have higher rates of screw loosening. Screw loosening can be asymptomatic and presents opportunity for osseous integration on later follow-up. Although adverse effects on clinical outcomes are rare, longer-term follow-up is required in cases in which screws become loose.
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Affiliation(s)
- Jau-Ching Wu
- 1Departments of Neurosurgery, Neurological Institute,
- 4School of Medicine, National Yang-Ming University; and
- 5Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan
| | - Wen-Cheng Huang
- 1Departments of Neurosurgery, Neurological Institute,
- 4School of Medicine, National Yang-Ming University; and
| | - Hsiao-Wen Tsai
- 2Obstetrics and Gynecology, and
- 4School of Medicine, National Yang-Ming University; and
| | - Chin-Chu Ko
- 1Departments of Neurosurgery, Neurological Institute,
- 4School of Medicine, National Yang-Ming University; and
| | - Ching-Lan Wu
- 3Radiology, Taipei Veterans General Hospital
- 4School of Medicine, National Yang-Ming University; and
| | - Tsung-Hsi Tu
- 1Departments of Neurosurgery, Neurological Institute,
- 4School of Medicine, National Yang-Ming University; and
- 5Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan
| | - Henrich Cheng
- 1Departments of Neurosurgery, Neurological Institute,
- 4School of Medicine, National Yang-Ming University; and
- 5Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan
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Browne JA, Hanssen AD. Reconstruction of patellar tendon disruption after total knee arthroplasty: results of a new technique utilizing synthetic mesh. J Bone Joint Surg Am 2011; 93:1137-43. [PMID: 21776550 DOI: 10.2106/jbjs.j.01036] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND Patellar tendon disruption associated with total knee arthroplasty is an uncommon but potentially disastrous complication. Repair with isolated suture fixation is insufficient, and autograft and allograft tendon reconstruction techniques have variable results. The purpose of this study was to determine the results of a novel surgical technique in which readily available synthetic mesh is used for patellar tendon reconstruction. METHODS We retrospectively reviewed thirteen consecutive patients who underwent extensor mechanism reconstruction for subacute or chronic patellar tendon disruption following total knee arthroplasty at an average age of sixty years (range, thirty-seven to seventy-seven years). Five patients had already been treated unsuccessfully with an allograft extensor mechanism reconstruction and eight had a prior revision knee arthroplasty. The surgical technique included use of a knitted monofilament polypropylene graft to reconstruct the patellar tendon and to facilitate fixation of adjacent host tissue into the graft. Follow-up was available for all patients at a mean of forty-two months (range, eleven to 118 months). RESULTS Three patients had evidence of failure of the graft reconstruction, all within six months. One patient with previous sepsis had recurrent infection and was treated with a knee arthrodesis. The remaining nine patients all demonstrated an extensor lag of no greater than 10° and have had no loss of extension at the time of final follow-up. Knee flexion was maintained in all patients (a mean of 103° preoperatively versus a mean of 107° postoperatively). The mean Knee Society scores for pain and function improved significantly (p < 0.01). Synthetic mesh was significantly less expensive than allograft for this reconstruction. CONCLUSIONS The use of synthetic mesh to reconstruct a disrupted patellar tendon is a straightforward surgical procedure that was successful and durable in the majority of patients in our series. Compared with the use of an allograft, this technique eliminates the possibility of disease transmission and may be more cost-effective. No complications unique to the synthetic mesh were observed.
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Affiliation(s)
- James A Browne
- Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
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Graves DT, Alblowi J, Paglia DN, O’Connor JP, Lin S. Impact of Diabetes on Fracture Healing. ACTA ACUST UNITED AC 2011. [DOI: 10.1016/j.jecm.2010.12.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Bedi A, Fox AJ, Harris PE, Deng XH, Ying L, Warren RF, Rodeo SA. Diabetes mellitus impairs tendon-bone healing after rotator cuff repair. J Shoulder Elbow Surg 2010; 19:978-88. [PMID: 20303293 PMCID: PMC5257255 DOI: 10.1016/j.jse.2009.11.045] [Citation(s) in RCA: 131] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2009] [Revised: 11/08/2009] [Accepted: 11/09/2009] [Indexed: 02/01/2023]
Abstract
INTRODUCTION Studies have demonstrated a significant decrease in skeletal mass, bone mineral density, and impaired fracture healing in the diabetic population. However, the effect of sustained hyperglycemia on tendon-to-bone healing is unknown. MATERIALS AND METHODS Forty-eight male, Lewis rats underwent unilateral detachment of the supraspinatus tendon followed by immediate anatomic repair with transosseous fixation. In the experimental group (n = 24), diabetes was induced preoperatively via intraperitoneal injection of streptozotocin (STZ, 65 mg/kg) and confirmed with both pre- and post-STZ injection intraperitoneal glucose tolerance tests (IPGTT). Animals were sacrificed at 1 and 2 weeks postoperatively for biomechanical, histomorphometric, and immunohistochemical analysis. Serum hemoglobin A1c (HbA1c) levels were measured at 2 weeks postoperatively. Statistical comparisons were performed using Student t tests with significance set at P < .05. RESULTS IPGTT analysis demonstrated a significant impairment of glycemic control in the diabetic compared to control animals (P < .05). Mean HbA1c level at 2 weeks postoperatively was 10.6 ± 2.7% and 6.0 ± 1.0% for the diabetic and control groups, respectively (P < .05). Diabetic animals demonstrated significantly less fibrocartilage and organized collagen, and increased AGE deposition at the tendon-bone interface (P < .05). The healing enthesis of diabetic animals demonstrated a significantly reduced ultimate load-to-failure (4.79 ± 1.33 N vs 1.60 ± 1.67 N and 13.63 ± 2.33 N vs 6.0 ± 3.24 N for control versus diabetic animals at 1 and 2 weeks, respectively) and stiffness compared to control animals (P < .05). DISCUSSION Sustained hyperglycemia impairs tendon-bone healing after rotator cuff repair in this rodent model. These findings have significant clinical implications for the expected outcomes of soft tissue repair or reconstructive procedures in diabetic patients with poor glycemic control.
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Affiliation(s)
- Asheesh Bedi
- Laboratory for Soft Tissue Research, Hospital for Special Surgery, New York, NY,Reprint requests: Asheesh Bedi, MD, Fellow, Sports Medicine & Shoulder Surgery, Laboratory for Soft Tissue Research, Hospital For Special Surgery, 535 East 70th Street. New York City, NY 10021. (A. Bedi)
| | - Alice J.S. Fox
- Laboratory for Soft Tissue Research, Hospital for Special Surgery, New York, NY
| | | | - Xiang-Hua Deng
- Laboratory for Soft Tissue Research, Hospital for Special Surgery, New York, NY
| | - Liang Ying
- Laboratory for Soft Tissue Research, Hospital for Special Surgery, New York, NY
| | - Russell F. Warren
- Laboratory for Soft Tissue Research, Hospital for Special Surgery, New York, NY
| | - Scott A. Rodeo
- Laboratory for Soft Tissue Research, Hospital for Special Surgery, New York, NY
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Mehta SK, Breitbart EA, Berberian WS, Liporace FA, Lin SS. Bone and wound healing in the diabetic patient. Foot Ankle Clin 2010; 15:411-37. [PMID: 20682414 DOI: 10.1016/j.fcl.2010.03.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Impaired soft tissue regeneration and delayed osseous healing are known complications associated with diabetes mellitus with regard to orthopedic surgery, making the management and treatment of diabetic patients undergoing foot and ankle surgery more complex and difficult. At the moment several options are available to address the known issues that complicate the clinical outcomes in these high-risk patients. Using a multifaceted approach, with close attention to intraoperative and perioperative considerations including modification of surgical technique to supplement fixation, local application of orthobiologics, tight glycemic control, administration of supplementary oxygen, and biophysical stimulation via low-intensity pulsed ultrasound and electrical bone stimulation, the impediments associated with diabetic healing can potentially be overcome, to yield improved clinical results for diabetic patients after acute or elective foot and ankle surgery.
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Affiliation(s)
- Siddhant K Mehta
- Department of Orthopaedics, University of Medicine and Dentistry of New Jersey, Newark, 07103, USA
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Abstract
Diabetes mellitus and, in particular, type 1 diabetes has been associated with impaired osseous wound healing properties. The scope of the present review is to discuss the clinical evidence supporting a higher rate of complications during fracture healing in diabetic patients and the histological evidence indicating impaired potential for intramembranous and endochondral ossification in the presence of uncontrolled experimental diabetes. The article further provides a synthesis of our current understanding of the plausible molecular mechanisms underlying the diabetic bone healing pathophysiology and of the role of insulin treatment in promoting osseous healing in the diabetic status.
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Affiliation(s)
- M Retzepi
- Periodontology Unit, Clinical Research Division, UCL Eastman Dental Institute, London, UK.
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Hanes PJ, Krishna R. Characteristics of inflammation common to both diabetes and periodontitis: are predictive diagnosis and targeted preventive measures possible? EPMA J 2010; 1:101-16. [PMID: 23199045 PMCID: PMC3405308 DOI: 10.1007/s13167-010-0016-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2009] [Accepted: 01/24/2010] [Indexed: 11/21/2022]
Abstract
Diabetes and periodontitis are chronic inflammatory disorders that contribute to each others' severity and worsen each others' prognosis. Studies have shown that patients with diabetes are at increased risk of developing periodontitis, and that diabetics with untreated periodontitis have more difficulty controlling serum glucose. Periodontal treatment that reduces gingival inflammation aids in the control of hyperglycemia. Periodontitis is accompanied by gingival bleeding and the production of an inflammatory exudate termed gingival crevicular fluid (GCF) that arises from the inflamed gingival tissues surrounding the teeth. GCF contains byproducts of connective tissue degradation, enzymes from host and bacterial cells, cytokines and other inflammatory mediators, and has been studied for screening blood glucose and for biomarkers of both diabetes and periodontitis. This review focuses on the inter-relationship between diabetes and periodontitis and the biomarkers common to both these diseases that may enable earlier detection, targeted preventive measures and individualized therapeutic intervention of these chronic conditions.
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Affiliation(s)
- Philip J. Hanes
- Department of Periodontics, Medical College of Georgia School of Dentistry, Augusta, GA 30912 USA
| | - Ranjitha Krishna
- Department of Periodontics, Medical College of Georgia School of Dentistry, Augusta, GA 30912 USA
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Kidder LS, Chen X, Schmidt AH, Lew WD. Osteogenic protein-1 overcomes inhibition of fracture healing in the diabetic rat: a pilot study. Clin Orthop Relat Res 2009; 467:3249-56. [PMID: 18663547 PMCID: PMC2772901 DOI: 10.1007/s11999-008-0405-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2007] [Accepted: 07/07/2008] [Indexed: 01/31/2023]
Abstract
Type I diabetes mellitus inhibits fracture healing and leads to an increase in complications. As a pilot study, we used a closed fracture model in the diabetic rat to address the question of whether osteogenic protein-1 (OP-1) in a collagen carrier can overcome this inhibition by increasing the area of the newly mineralized callus and femoral torque to failure compared with diabetic animals with fractures treated without OP-1. Diabetes was created in 54 rats by injection of streptozotocin. After 2 weeks, a closed femur fracture was created using a drop-weight impaction device. Each fracture site was immediately opened and treated with or without 25 microg OP-1 in a collagen carrier. Animals were euthanized after 2 or 4 weeks. Fracture healing was assessed by callus area from high-resolution radiographs, callus strength from torsional failure testing, and undecalcified histologic analysis. The area of newly mineralized callus was greater in diabetic animals treated with 25 microg OP-1/carrier compared with diabetic animals with untreated fractures and with fractures treated with carrier alone. This increase in callus area did not translate into an equivalent increase in torque to failure. Osteogenic protein-1 showed some evidence of overcoming the inhibition of fracture healing in the diabetic rat.
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Affiliation(s)
- Louis S. Kidder
- Orthopaedic Biomechanics Laboratory, Midwest Orthopaedic Research Foundation, Minneapolis, MN USA ,Department of Radiology, University of Minnesota School of Medicine, Mayo Mail Code B292, 420 Delaware Street SE, Minneapolis, MN 55455 USA
| | - Xinqian Chen
- Orthopaedic Biomechanics Laboratory, Midwest Orthopaedic Research Foundation, Minneapolis, MN USA
| | - Andrew H. Schmidt
- Orthopaedic Surgery Department, Hennepin County Medical Center, Minneapolis, MN USA
| | - William D. Lew
- Orthopaedic Biomechanics Laboratory, Midwest Orthopaedic Research Foundation, Minneapolis, MN USA
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Alblowi J, Kayal RA, Siqueira M, Siqueria M, McKenzie E, Krothapalli N, McLean J, Conn J, Nikolajczyk B, Einhorn TA, Gerstenfeld L, Graves DT. High levels of tumor necrosis factor-alpha contribute to accelerated loss of cartilage in diabetic fracture healing. THE AMERICAN JOURNAL OF PATHOLOGY 2009; 175:1574-85. [PMID: 19745063 DOI: 10.2353/ajpath.2009.090148] [Citation(s) in RCA: 116] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Diabetes interferes with fracture repair; therefore, we investigated mechanisms of impaired fracture healing in a model of multiple low-dose streptozotocin-induced diabetes. Microarray and gene set enrichment analysis revealed an up-regulation of gene sets related to inflammation, including tumor necrosis factor (TNF) signaling in the diabetic group, when cartilage is being replaced by bone on day 16, but not on days 12 or 22. This change coincided with elevated osteoclast numbers and accelerated removal of cartilage in the diabetic group (P < 0.05), which was reflected by smaller callus size. When diabetic mice were treated with the TNF-specific inhibitor, pegsunercept, the number of osteoclasts, cartilage loss, and number of TNF-alpha and receptor activator for nuclear factor kB ligand positive chondrocytes were significantly reduced (P < 0.05). The transcription factor forkhead box 01 (FOXO1) was tested for mediating TNF stimulation of osteoclastogenic and inflammatory factors in bone morphogenetic protein 2 pretreated ATDC5 and C3H10T1/2 chondrogenic cells. FOXO1 knockdown by small-interfering RNA significantly reduced TNF-alpha, receptor activator for nuclear factor kB ligand, macrophage colony-stimulating factor, interleukin-1alpha, and interleukin-6 mRNA compared with scrambled small-interfering RNA. An association between FOXO1 and the TNF-alpha promoter was demonstrated by chromatin immunoprecipitation assay. Moreover, diabetes increased FOXO1 nuclear translocation in chondrocytes in vivo and increased FOXO1 DNA binding activity in diabetic fracture calluses (P < 0.05). These results suggest that diabetes-enhanced TNF-alpha increases the expression of resorptive factors in chondrocytes through a process that involves activation of FOXO1 and that TNF-alpha dysregulation leads to enhanced osteoclast formation and accelerated loss of cartilage.
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Affiliation(s)
- Jazia Alblowi
- Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, Massachusetts, USA
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Oates TW, Dowell S, Robinson M, McMahan CA. Glycemic control and implant stabilization in type 2 diabetes mellitus. J Dent Res 2009; 88:367-71. [PMID: 19407159 DOI: 10.1177/0022034509334203] [Citation(s) in RCA: 117] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Diabetes mellitus is considered a relative contra-indication for implant therapy. However, the effect of glycemic level on implant integration in persons with diabetes remains poorly understood. The hypothesis of this research was that poor glycemic control is directly related to short-term-impairment implant stabilization. This prospective clinical study evaluated 10 non-diabetic individuals (12 implants) and 20 persons with type 2 diabetes (30 implants). Glycated hemoglobin (HbA1c) levels ranged from 4.7-12.6%. Implant stability was assessed by resonance frequency analysis over 4 months following placement. Minimum stability levels were observed 2-6 weeks following placement for all 42 implants. Persons with HbA1c > or = 8.1% had a greater maximum decrease in stability from baseline and required a longer time for healing, as indicated by return of stability level to baseline. This study demonstrates alterations in implant stability consistent with impaired implant integration for persons with type 2 diabetes mellitus in direct relation to hyperglycemic conditions.
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Affiliation(s)
- T W Oates
- Department of Periodontics, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
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Kayal RA, Alblowi J, McKenzie E, Krothapalli N, Silkman L, Gerstenfeld L, Einhorn TA, Graves DT. Diabetes causes the accelerated loss of cartilage during fracture repair which is reversed by insulin treatment. Bone 2009; 44:357-63. [PMID: 19010456 PMCID: PMC2700945 DOI: 10.1016/j.bone.2008.10.042] [Citation(s) in RCA: 100] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2008] [Revised: 10/01/2008] [Accepted: 10/14/2008] [Indexed: 11/15/2022]
Abstract
Fracture healing in diabetic individuals and in animal models of diabetes is impaired. To investigate mechanisms by which diabetes may affect fracture healing we focused on the transition from cartilage to bone, a midpoint in the fracture healing process. Femoral fractures were induced in mice rendered diabetic by multiple low dose streptozotocin treatment and compared to matching normoglycemic mice. One group of diabetic animals was treated with slow release insulin to maintain normal serum glucose levels. The results indicate that there was relatively little difference in the initial formation of the fracture callus on day 10. However, on day 16 the diabetic group had significantly smaller callus, greater loss of cartilage and enhanced osteoclastogenesis that was normalized by treatment with insulin when assessed by histomorphometric analysis. Chondrocyte apoptosis was significantly higher in diabetic mice and this increase was blocked by insulin. These changes were accompanied by diabetes-increased mRNA levels of RANKL, TNF-alpha, and ADAMTS-4 and -5 measured by real-time PCR, which was reversed by insulin treatment. On days 16 and 22 bone formation within the callus of diabetic mice was significantly less than the normoglycemic and brought to normal levels by insulin treatment. These results suggest that a significant effect of diabetes on fracture healing is increased chondrocyte apoptosis and osteoclastogenesis that accelerates the loss of cartilage and reduces the anlage for endochondral bone formation during fracture repair. That insulin reverses these effects demonstrates that they are directly related to the diabetic condition.
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Affiliation(s)
- Rayyan A. Kayal
- Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, MA 02118, USA
| | - Jazia Alblowi
- Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, MA 02118, USA
| | - Erin McKenzie
- Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, MA 02118, USA
| | - Nanarao Krothapalli
- Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, MA 02118, USA
| | - Lee Silkman
- Department of Orthopedic Surgery, Boston University School of Medicine, Boston, MA 02118, USA
| | - Louis Gerstenfeld
- Department of Orthopedic Surgery, Boston University School of Medicine, Boston, MA 02118, USA
| | - Thomas A. Einhorn
- Department of Orthopedic Surgery, Boston University School of Medicine, Boston, MA 02118, USA
| | - Dana T. Graves
- Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, MA 02118, USA
- Corresponding author. E-mail address: (D.T. Graves)
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Raunio T, Knuuttila M, Hiltunen L, Karttunen R, Vainio O, Tervonen T. IL-6−174genotype associated with the extent of periodontal disease in type 1 diabetic subjects. J Clin Periodontol 2009; 36:11-7. [DOI: 10.1111/j.1600-051x.2008.01344.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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