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Manochantr S, Meesuk L, Chadee N, Suwanprateeb J, Tantrawatpan C, Kheolamai P. Improvement of osteogenic differentiation potential of placenta-derived mesenchymal stem cells by metformin via AMPK pathway activation. Stem Cell Res Ther 2024; 15:417. [PMID: 39533406 PMCID: PMC11559138 DOI: 10.1186/s13287-024-04014-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Placenta-derived human mesenchymal stem cells (PL-MSCs) have gained a lot of attention in the field of regenerative medicine due to their availability and bone-forming capacity. However, the osteogenic differentiation capacity of these cells remains inconsistent and could be improved to achieve greater efficiency. Although metformin, a widely used oral hypoglycemic agent, has been shown to increase bone formation in various cell types, its effect on osteogenic differentiation of PL-MSCs has not yet been investigated. Therefore, the objective of this study was to examine the effect of metformin on the osteogenic differentiation capacity of PL-MSCs and the underlying mechanisms. METHODS The PL-MSCs were treated with 0.5 to 640 µM metformin and their osteogenic differentiation capacity was examined by an alkaline phosphatase (ALP) activity assay, Alizarin red S staining and expression levels of osteogenic genes. The role of adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling in mediating the effect of metformin on the osteogenic differentiation capacity of PL-MSCs was also investigated by determining levels of phosphorylated AMPK (pAMPK)/AMPK ratio and by using compound C, an AMPK inhibitor. RESULTS The results showed that 10-160 µM metformin significantly increased the viability of PL-MSCs in a dose- and time-dependent manner. Furthermore, 80-320 µM metformin also increased ALP activity, matrix mineralization, and expression levels of osteogenic genes, runt-related transcription factor 2 (RUNX2), osterix (OSX), osteocalcin (OCN) and collagen I (COL1), in PL-MSCs. Metformin increases osteogenic differentiation of PL-MSCs, at least in part, through the AMPK signaling pathway, since the administration of compound C inhibited its enhancing effects on ALP activity, matrix mineralization, and osteogenic gene expression of PL-MSCs. CONCLUSIONS This study demonstrated that metformin at concentrations of 80-320 μM significantly enhanced osteogenic differentiation of PL-MSCs in a dose- and time-dependent manner, primarily through activation of the AMPK signaling pathway. This finding suggests that metformin could be used with other conventional drugs to induce bone regeneration in various bone diseases. Additionally, this study provides valuable insights for future osteoporosis treatment by highlighting the potential of modulating the AMPK pathway to improve bone regeneration.
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Affiliation(s)
- Sirikul Manochantr
- Division of Cell Biology, Department of Preclinical Sciences, Faculty of Medicine, Thammasat University, KhlongLuang, Pathum Thani, 12120, Thailand.
- Center of Excellence in Stem Research and Innovation, Thammasat University, KhlongLuang, Pathum Thani, 12120, Thailand.
| | - Ladda Meesuk
- Division of Cell Biology, Department of Preclinical Sciences, Faculty of Medicine, Thammasat University, KhlongLuang, Pathum Thani, 12120, Thailand
| | - Nuengruethai Chadee
- Division of Cell Biology, Department of Preclinical Sciences, Faculty of Medicine, Thammasat University, KhlongLuang, Pathum Thani, 12120, Thailand
| | - Jintamai Suwanprateeb
- Biomedical Engineering Research Unit, National Metal and Materials Technology Center (MTEC), Ministry of Science and Technology, Khlong Nueng, 12120, Pathum Thani, Thailand
| | - Chairat Tantrawatpan
- Division of Cell Biology, Department of Preclinical Sciences, Faculty of Medicine, Thammasat University, KhlongLuang, Pathum Thani, 12120, Thailand
- Center of Excellence in Stem Research and Innovation, Thammasat University, KhlongLuang, Pathum Thani, 12120, Thailand
| | - Pakpoom Kheolamai
- Division of Cell Biology, Department of Preclinical Sciences, Faculty of Medicine, Thammasat University, KhlongLuang, Pathum Thani, 12120, Thailand
- Center of Excellence in Stem Research and Innovation, Thammasat University, KhlongLuang, Pathum Thani, 12120, Thailand
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Zhang X, Xu J. The effect of coffee consumption on three main bone disorders: a Mendelian randomization trial. J Bone Miner Metab 2024; 42:633-646. [PMID: 38985180 DOI: 10.1007/s00774-024-01533-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 06/12/2024] [Indexed: 07/11/2024]
Abstract
INTRODUCTION Despite a large number of observational studies examining the effect of coffee consumption(CC) on bone disorders(BDs), particularly, osteoarthritis(OA), osteoportic fracture(OF), and rheumatoid arthritis(RA), the conclusions are highly controversial. Thus, it is essential to examine the causal association between CC and BDs. MATERIALS AND METHODS Mendelian randomization (MR) analysis was performed to assess the causal influence of CC on OF, RA, and OA. The main endpoint was the odds ratio (OR) of the inverse variance weighted (IVW) approach. In addition, the weighted median (WM), MR-Egger regressions, MR-pleiotropy residual sum and outlier (MR-PRESSO) and multivariable MR (MVMR) were included in sensitivity analyses. Furthermore, the function of causal SNPs was evaluated by gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction networks. RESULTS Primary MR analysis based on the IVW method suggested that changes in CC alter risk of OF (OR = 1.383, 95%CI 1.079-1.853, P = 0.039), RA(OR: 1.623, 95%CI 1.042-2.527, P = 0.032) and HOA (hip osteoarthritis, OR = 1.536, 95% CI 1.044-2.259, P = 0.021). However, these causal relationships were not robust in sensitivity analyses. In contrast, there is a positive causal relationship between increased CC and the risk of KOA (knee osteoarthritis, OR: 2.094, 95%CI: 1.592-2.754, P = 1.41 × 10-7), as evidenced by the IVW using random effect. A similar effect size was observed across all MR sensitivity analyses, with no evidence of horizontal pleiotropy. CONCLUSION Based on our MR analysis, increased CC was causally linked to an increase in the risk of KOA. Genetic predictions suggested that CC reduction may have benefits for bone health.
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Affiliation(s)
- Xiang Zhang
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, 250021, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, 250021, Shandong, China
| | - Jin Xu
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, 250021, Shandong, China.
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, 250021, Shandong, China.
- Chuangxin China" Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases, Jinan, 250021, Shandong, China.
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, 250021, Shandong, China.
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, 250021, Shandong, China.
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Aldukhayel A. Prevalence and patterns of bone mineral density disorders among women in Buraidah, KSA. J Taibah Univ Med Sci 2023; 18:348-355. [PMID: 37102077 PMCID: PMC10124114 DOI: 10.1016/j.jtumed.2022.09.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 09/09/2022] [Accepted: 09/16/2022] [Indexed: 02/04/2023] Open
Abstract
Objectives Bone mineral density (BMD) disorders are disorders of bone mineralization in which bone density is reduced (T score <-1). BMD causes health and social burdens on individuals and communities. This study estimated the prevalence and determined the patterns of BMD disorders among women in Buraidah, KSA. Methods A cross-sectional study was conducted in 342 women visiting the DEXA Scanning Center in Buraidah. Dual-energy X-ray absorptiometry (DEXA) scan was used to measure the BMD, and cutoffs were defined based on World Health Organization criteria: normal = T score >-1, osteopenia = T score <-1 to >-2.5, and osteoporosis = T score ≤-2.5. Sociodemographic and health-related data were collected. Logistic regression was used to measure the association of various participant characteristics with BMD disorders. Results The mean age of the participants was 61.2 ± 7.54 years. The overall prevalence of BMD disorders was 76%, of whom 42% had osteopenia, 24% had both osteoporosis and osteopenia, and 10% had osteoporosis. Body mass index, menopause, hypertension, oral hypoglycemics, and calcium supplementation were significant predictors of BMD disorders. Conclusions The high prevalence of BMD disorders among women in KSA necessitates establishing and strengthening osteoporosis prevention programs to ensure healthy aging among women in KSA. Large-scale community-based studies are needed to accurately estimate the burden and risk factors of BMD disorders in the community.
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Ker A, Kao PE. Correspondence on “low cumulative disease activity is associated with higher bone mineral density in a majority Latinx and Asian US rheumatoid arthritis cohort” by Wysham et al. Semin Arthritis Rheum 2022; 54:152000. [DOI: 10.1016/j.semarthrit.2022.152000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 03/22/2022] [Indexed: 10/18/2022]
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The Effects of Photobiomodulation on Bone Defect Repairing in a Diabetic Rat Model. Int J Mol Sci 2021; 22:ijms222011026. [PMID: 34681687 PMCID: PMC8541159 DOI: 10.3390/ijms222011026] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 10/09/2021] [Accepted: 10/10/2021] [Indexed: 11/17/2022] Open
Abstract
The purpose of this study is to examine the prospective therapeutic effects of photobiomodulation on the healing of bone defects in diabetic mellitus (DM) using rat models to provide basic knowledge of photobiomodulation therapy (PBMT) during bone defect repair. For in vitro study, an Alizzarin red stain assay was used to evaluate the effect of PBMT on osteogenic differentiation. For in vivo study, micro-computed tomography (microCT) scan, H&E and IHC stain analysis were used to investigate the effect of PBMT on the healing of the experimental calvarial defect (3 mm in diameter) of a diabetic rat model. For in vitro study, the high glucose groups showed lower osteogenic differentiation in both irradiated and non-irradiated with PBMT when compared to the control groups. With the PBMT, all groups (control, osmotic control and high glucose) showed higher osteogenic differentiation when compared to the non-irradiated groups. For in vivo study, the hyperglycemic group showed significantly lower bone regeneration when compared to the control group. With the PBMT, the volume of bone regeneration was increasing and back to the similar level of the control group. The treatment of PBMT in 660 nm could improve the bone defect healing on a diabetic rat calvarial defect model.
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Abstract
PURPOSE OF REVIEW Patients with diabetes mellitus (DM) are at increased risk of developing osteopathogenesis and skeletal fragility. The role of the gut microbiota in both DM and osteopathy is not fully explored and may be involved in the pathology of both diseases. RECENT FINDINGS Gut microbiota alterations have been observed in DM and osteopathogenic disorders as compared with healthy controls, such as significantly lower abundance of Prevotella and higher abundance of Lactobacillus, with a diminished bacterial diversity. Other overlapping gastro-intestinal features include the loss of intestinal barrier function with translocation of bacterial metabolites to the blood stream, induction of immunological deficits and changes in hormonal and endocrinal signalling, which may lead to the development of diabetic osteopathy. Signalling pathways involved in both DM and osteopathy are affected by gut bacteria and their metabolites. Future studies should focus on gut microbiota involvement in both diseases.
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Affiliation(s)
- Julie Kristine Knudsen
- Centre for Clinical Research, North Denmark Regional Hospital, Bispensgade 37, 9800, Hjørring, Denmark.
- Department of Clinical Medicine, Aalborg University, Søndre Skovvej 15, Aalborg, Denmark.
| | - Peter Leutscher
- Centre for Clinical Research, North Denmark Regional Hospital, Bispensgade 37, 9800, Hjørring, Denmark
- Department of Clinical Medicine, Aalborg University, Søndre Skovvej 15, Aalborg, Denmark
- Steno Diabetes Center North Jutland, Mølleparkvej 4, Aalborg, Denmark
| | - Suzette Sørensen
- Centre for Clinical Research, North Denmark Regional Hospital, Bispensgade 37, 9800, Hjørring, Denmark
- Department of Clinical Medicine, Aalborg University, Søndre Skovvej 15, Aalborg, Denmark
- Steno Diabetes Center North Jutland, Mølleparkvej 4, Aalborg, Denmark
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Bhatti FUR, Dadwal UC, Valuch CR, Tewari NP, Awosanya OD, de Andrade Staut C, Sun S, Mendenhall SK, Perugini AJ, Nagaraj RU, Battina HL, Nazzal MK, Blosser RJ, Maupin KA, Childress PJ, Li J, Kacena MA. The effects of high fat diet, bone healing, and BMP-2 treatment on endothelial cell growth and function. Bone 2021; 146:115883. [PMID: 33581374 PMCID: PMC8009863 DOI: 10.1016/j.bone.2021.115883] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 02/06/2021] [Accepted: 02/08/2021] [Indexed: 02/08/2023]
Abstract
Angiogenesis is a vital process during the regeneration of bone tissue. The aim of this study was to investigate angiogenesis at the fracture site as well as at distal locations from obesity-induced type 2 diabetic mice that were treated with bone morphogenetic protein-2 (BMP-2, local administration at the time of surgery) to heal a femoral critical sized defect (CSD) or saline as a control. Mice were fed a high fat diet (HFD) to induce a type 2 diabetic-like phenotype while low fat diet (LFD) animals served as controls. Endothelial cells (ECs) were isolated from the lungs (LECs) and bone marrow (BMECs) 3 weeks post-surgery, and the fractured femurs were also examined. Our studies demonstrate that local administration of BMP-2 at the fracture site in a CSD model results in complete bone healing within 3 weeks for all HFD mice and 66.7% of LFD mice, whereas those treated with saline remain unhealed. At the fracture site, vessel parameters and adipocyte numbers were significantly increased in BMP-2 treated femurs, irrespective of diet. At distal sites, LEC and BMEC proliferation was not altered by diet or BMP-2 treatment. HFD increased the tube formation ability of both LECs and BMECs. Interestingly, BMP-2 treatment at the time of surgery reduced tube formation in LECs and humeri BMECs. However, migration of BMECs from HFD mice treated with BMP-2 was increased compared to BMECs from HFD mice treated with saline. BMP-2 treatment significantly increased the expression of CD31, FLT-1, and ANGPT2 in LECs and BMECs in LFD mice, but reduced the expression of these same genes in HFD mice. To date, this is the first study that depicts the systemic influence of fracture surgery and local BMP-2 treatment on the proliferation and angiogenic potential of ECs derived from the bone marrow and lungs.
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Affiliation(s)
- Fazal Ur Rehman Bhatti
- Department of Orthopaedic Surgery, Indiana University School of Medicine, IN, USA; Richard L. Roudebush VA Medical Center, IN, USA
| | - Ushashi C Dadwal
- Department of Orthopaedic Surgery, Indiana University School of Medicine, IN, USA; Richard L. Roudebush VA Medical Center, IN, USA
| | - Conner R Valuch
- Department of Biology, Indiana University Purdue University Indianapolis, IN, USA
| | - Nikhil P Tewari
- Department of Orthopaedic Surgery, Indiana University School of Medicine, IN, USA
| | - Olatundun D Awosanya
- Department of Orthopaedic Surgery, Indiana University School of Medicine, IN, USA
| | | | - Seungyup Sun
- Department of Orthopaedic Surgery, Indiana University School of Medicine, IN, USA
| | - Stephen K Mendenhall
- Department of Orthopaedic Surgery, Indiana University School of Medicine, IN, USA
| | - Anthony J Perugini
- Department of Orthopaedic Surgery, Indiana University School of Medicine, IN, USA
| | - Rohit U Nagaraj
- Department of Orthopaedic Surgery, Indiana University School of Medicine, IN, USA
| | - Hanisha L Battina
- Department of Orthopaedic Surgery, Indiana University School of Medicine, IN, USA
| | - Murad K Nazzal
- Department of Orthopaedic Surgery, Indiana University School of Medicine, IN, USA
| | - Rachel J Blosser
- Department of Orthopaedic Surgery, Indiana University School of Medicine, IN, USA; Richard L. Roudebush VA Medical Center, IN, USA
| | - Kevin A Maupin
- Department of Orthopaedic Surgery, Indiana University School of Medicine, IN, USA
| | - Paul J Childress
- Department of Orthopaedic Surgery, Indiana University School of Medicine, IN, USA; Richard L. Roudebush VA Medical Center, IN, USA
| | - Jiliang Li
- Department of Biology, Indiana University Purdue University Indianapolis, IN, USA
| | - Melissa A Kacena
- Department of Orthopaedic Surgery, Indiana University School of Medicine, IN, USA; Richard L. Roudebush VA Medical Center, IN, USA.
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Lakatos P, Szili B, Bakos B, Takacs I, Putz Z, Istenes I. Thyroid Hormones, Glucocorticoids, Insulin, and Bone. Handb Exp Pharmacol 2020; 262:93-120. [PMID: 32036458 DOI: 10.1007/164_2019_314] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Several endocrine systems have important effects on bone tissue. Thyroid hormones are essential for normal growth and development. Excess of these hormones will result in clinically significant changes that may require intervention. Glucocorticoids also have a marked effect on bone metabolism by several pathways. Their endogenous or exogenous excess will induce pathological processes that might elevate the risk of fractures. Insulin and the carbohydrate metabolism elicit a physiological effect on bone; however, the lack of insulin (type 1 diabetes) or insulin resistance (type 2 diabetes) have deleterious influence on bone tissue.
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Affiliation(s)
- Peter Lakatos
- 1st Department of Medicine, Semmelweis University, Budapest, Hungary.
| | - Balazs Szili
- 1st Department of Medicine, Semmelweis University, Budapest, Hungary
| | - Bence Bakos
- 1st Department of Medicine, Semmelweis University, Budapest, Hungary
| | - Istvan Takacs
- 1st Department of Medicine, Semmelweis University, Budapest, Hungary
| | - Zsuzsanna Putz
- 1st Department of Medicine, Semmelweis University, Budapest, Hungary
| | - Ildiko Istenes
- 1st Department of Medicine, Semmelweis University, Budapest, Hungary
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Wang C, Liu Y, Pan Y, Jin H. Effect of GSK-137647A, the first non-carboxylic FFA4 agonist, on the osteogenic and adipogenic differentiation of bone mesenchymal stem cells in db/db mice. ACTA ACUST UNITED AC 2019; 72:461-469. [PMID: 31858612 DOI: 10.1111/jphp.13217] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Accepted: 11/29/2019] [Indexed: 12/19/2022]
Abstract
OBJECTIVE To investigate the effect of GSK-137647A, the first non-carboxylic FFA4 agonist, on osteogenic and adipogenic differentiation of bone mesenchymal stem cells (BMSCs) of db/db mice. METHODS Bone mesenchymal stem cells were extracted from 8-week-old db/db mice. Cell Counting Kit-8 was used to evaluate the toxicity of GSK-137647A on BMSCs, and the optimal concentration of GSK-137647A was selected to investigate the osteogenic and adipogenic differentiation of BMSCs, and relevant indicators of osteoblasts and adipocytes were detected. KEY FINDINGS GSK-137647A had no significant toxicity on cell growth and proliferation. Moreover, GSK-137647A showed a significant increase in mineralization of BMSCs differentiated osteoblasts compared to the control group and elevated the alkaline phosphatase (ALP) activity in a time-dependent manner. Meanwhile, the treatment of GSK-137647A decreased the adipogenic differentiation of BMSCs. The expression levels of ALP, runt-related transcription factor 2, bone morphogenetic protein 4, osterix and β-catenin were significantly increased in GSK-137647A-treated group, while the gene and protein levels of peroxisome proliferator-activated receptor γ and CCAAT/enhancer binding protein α were significantly reduced. CONCLUSIONS All of these results demonstrated that GSK-137647A suppressed the adipogenic differentiation and promoted osteogenic differentiation of BMSCs, which is partly attributed to the increased expression of β-catenin in wingless/integrated signalling pathway.
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Affiliation(s)
- Chunlei Wang
- Department of Endocrinology, Yancheng City No. 1 People's Hospital, Yancheng, Jiangsu, China
| | - Yanmei Liu
- Department of Endocrinology, Yancheng City No. 1 People's Hospital, Yancheng, Jiangsu, China
| | - Yuan Pan
- Department of Science and Education, Yancheng Third People's Hospital, Yancheng, Jiangsu, China
| | - Hui Jin
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, Medical School, Southeast University, Nanjing, Jiangsu, China
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Kubo Y, Wruck CJ, Fragoulis A, Drescher W, Pape HC, Lichte P, Fischer H, Tohidnezhad M, Hildebrand F, Pufe T, Jahr H. Role of Nrf2 in Fracture Healing: Clinical Aspects of Oxidative Stress. Calcif Tissue Int 2019; 105:341-352. [PMID: 31236620 DOI: 10.1007/s00223-019-00576-3] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Accepted: 06/18/2019] [Indexed: 12/20/2022]
Abstract
Fracture healing is a natural process that recapitulates embryonic skeletal development. In the early phase after fracture, reactive oxygen species (ROS) are produced under inflammatory and ischemic conditions due to vessel injury and soft tissue damage, leading to cell death. Usually, such damage during the course of fracture healing can be largely prevented by protective mechanisms and functions of antioxidant enzymes. However, intrinsic oxidative stress can cause excessive toxic radicals, resulting in irreversible damage to cells associated with bone repair during the fracture healing process. Clinically, patients with type-2 diabetes mellitus, osteoporosis, habitual drinkers, or heavy smokers are at risk of impaired fracture healing due to elevated oxidative stress. Although increased levels of oxidative stress markers upon fracture and effects of antioxidants on fracture healing have been reported, a detailed understanding of what causes impaired fracture healing under intrinsic conditions of oxidative stress is lacking. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been identified as a key transcriptional regulator of the expression of antioxidants and detoxifying enzymes. It further not only plays a crucial role in preventing degenerative diseases in multiple organs, but also during fracture healing. This narrative review evaluates the influence of intrinsic oxidative stress on fracture healing and sheds new light on the intriguing role of Nrf2 during bone regeneration in pathological fractures.
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Affiliation(s)
- Yusuke Kubo
- Department of Anatomy and Cell Biology, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany.
| | - Christoph Jan Wruck
- Department of Anatomy and Cell Biology, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany
| | - Athanassios Fragoulis
- Department of Anatomy and Cell Biology, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany
| | - Wolf Drescher
- Department of Orthopaedics, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany
- Department of Orthopaedic Surgery of the Lower Limb and Arthroplasty, Hospital Rummelsberg, Rummelsberg 71, 90592, Schwarzenbruck, Germany
| | - Hans Christoph Pape
- Department of Trauma Surgery, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland
| | - Philipp Lichte
- Department of Orthopaedic Trauma Surgery, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Horst Fischer
- Department of Dental Materials and Biomaterials Research, RWTH Aachen University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Mersedeh Tohidnezhad
- Department of Anatomy and Cell Biology, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany
| | - Frank Hildebrand
- Department of Orthopaedic Trauma Surgery, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Thomas Pufe
- Department of Anatomy and Cell Biology, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany
| | - Holger Jahr
- Department of Anatomy and Cell Biology, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany
- Department of Orthopaedic Surgery, Maastricht University Medical Center+, 6229 HX Maastricht, The Netherlands
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Wei J, Zhang L, Ding Y, Liu R, Guo Y, Hettinghouse A, Buza J, De La Croix J, Li X, Einhorn TA, Liu CJ. Progranulin promotes diabetic fracture healing in mice with type 1 diabetes. Ann N Y Acad Sci 2019; 1460:43-56. [PMID: 31423598 DOI: 10.1111/nyas.14208] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Accepted: 07/18/2019] [Indexed: 12/21/2022]
Abstract
Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by insulin deficiency, and patients with diabetes have an increased risk of bone fracture and significantly impaired fracture healing. Proinflammatory cytokine tumor necrosis factor-alpha is significantly upregulated in diabetic fractures and is believed to underlie delayed fracture healing commonly observed in diabetes. Our previous genetic screen for the binding partners of progranulin (PGRN), a growth factor-like molecule that induces chondrogenesis, led to the identification of tumor necrosis factor receptors (TNFRs) as the PGRN-binding receptors. In this study, we employed several in vivo models to ascertain whether PGRN has therapeutic effects in diabetic fracture healing. Here, we report that deletion of PGRN significantly delayed bone fracture healing and aggravated inflammation in the fracture models of mice with T1DM. In contrast, recombinant PGRN effectively promoted diabetic fracture healing by inhibiting inflammation and enhancing chondrogenesis. In addition, both TNFR1 proinflammatory and TNFR2 anti-inflammatory signaling pathways are involved in PGRN-stimulated diabetic fracture healing. Collectively, these findings illuminate a novel understanding concerning the role of PGRN in diabetic fracture healing and may have an application in the development of novel therapeutic intervention strategies for diabetic and other types of impaired fracture healing.
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Affiliation(s)
- Jianlu Wei
- Department of Orthopaedic Surgery, New York University School of Medicine, New York University Medical Center, New York, New York.,Department of Orthopaedic Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Lei Zhang
- Department of Orthopaedic Surgery, New York University School of Medicine, New York University Medical Center, New York, New York.,Department of Orthopaedics, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, Jinan, Shandong, China
| | - Yuanjing Ding
- Department of Orthopaedic Surgery, New York University School of Medicine, New York University Medical Center, New York, New York
| | - Ronghan Liu
- Department of Orthopaedic Surgery, New York University School of Medicine, New York University Medical Center, New York, New York
| | - Yuqi Guo
- College of Dentistry, New York University, New York, New York
| | - Aubryanna Hettinghouse
- Department of Orthopaedic Surgery, New York University School of Medicine, New York University Medical Center, New York, New York
| | - John Buza
- Department of Orthopaedic Surgery, New York University School of Medicine, New York University Medical Center, New York, New York
| | - Jean De La Croix
- Department of Orthopaedic Surgery, New York University School of Medicine, New York University Medical Center, New York, New York
| | - Xin Li
- College of Dentistry, New York University, New York, New York
| | - Thomas A Einhorn
- Department of Orthopaedic Surgery, New York University School of Medicine, New York University Medical Center, New York, New York
| | - Chuan-Ju Liu
- Department of Orthopaedic Surgery, New York University School of Medicine, New York University Medical Center, New York, New York.,Department of Cell Biology, New York University School of Medicine, New York, New York
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Hosseinabadi MB, Khanjani N. The Effect of Extremely Low‐Frequency Electromagnetic Fields on the Prevalence of Musculoskeletal Disorders and the Role of Oxidative Stress. Bioelectromagnetics 2019; 40:354-360. [DOI: 10.1002/bem.22198] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 05/08/2019] [Indexed: 12/25/2022]
Affiliation(s)
| | - Narges Khanjani
- Environmental Health Engineering Research CentreKerman University of Medical SciencesKerman Iran
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13
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Yang HY, Lee HS, Huang WT, Chen MJ, Chen SCC, Hsu YH. Increased risk of fractures in patients with polycystic ovary syndrome: a nationwide population-based retrospective cohort study. J Bone Miner Metab 2018; 36:741-748. [PMID: 29280078 DOI: 10.1007/s00774-017-0894-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 11/25/2017] [Indexed: 12/18/2022]
Abstract
Polycystic ovary syndrome (PCOS) is a complex disorder; various features of this disorder may influence bone metabolism and skeletal mass. The contribution of PCOS to lower bone mineral density has been recognized. However, the impact of PCOS on the long-term risks for fractures remains inconclusive. The aim of this study was to determine the risk of overall fracture and fractures at different anatomic sites in patients with PCOS. Using a nationwide health insurance claims database, we included 11,106 subjects, aged 15-80 years, with newly diagnosed PCOS (ICD-9-CM: 254.4X) during 2000-2012. Patients with PCOS and respective age-matched (1:4) controls without PCOS were enrolled. The occurrence of fracture was monitored until the end of 2013. Cox regression and computed hazard ratios (HR) with 95% confidence intervals (95% CI) were used to determine the risk of PCOS among women with fractures. The PCOS and non-PCOS groups were comprised of 11,106 patients with PCOS and 44,424 participants without PCOS, respectively. Patients with PCOS had a higher incidence of any fractures compared with non-PCOS group (10.16 versus 8.07 per 1000 person-years) and a greater risk of any fractures [adjusted hazard ratio (aHR) = 1.23, 95% CI = 1.13-1.33], osteoporotic fractures (aHR = 1.33, 95% CI = 1.15-1.54), spine fractures (aHR = 1.36, 95% CI = 1.11-1.66) and forearm fractures (aHR = 1.39, 95% CI = 1.07-1.80), but the risk for femur or hip fracture, humerus, wrist and non-osteoporotic fractures were not increased. In conclusion, the PCOS group had a higher occurrence rate of fractures than the non-PCOS group. These results provide evidence for the adverse effects of PCOS on the risk of fractures.
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Affiliation(s)
- Hsin-Yi Yang
- Clinical Medicine Research Center, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, 600, Taiwan
| | - Herng-Sheng Lee
- Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, 813, Taiwan
| | - Wan-Ting Huang
- Clinical Medicine Research Center, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, 600, Taiwan
| | - Ming-Jer Chen
- Department of Obstetrics and Gynecology and Women's Health, Taichung Veterans General Hospital, Taichung, 407, Taiwan
| | - Solomon Chih-Cheng Chen
- Heng Chun Christian Hospital, Pingtung County, 946, Taiwan
- Department of Pediatrics, School of Medicine, Taipei Medical University, Taipei, 110, Taiwan
| | - Yueh-Han Hsu
- Clinical Medicine Research Center, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, 600, Taiwan.
- Department of Medical Research, China Medical University Hospital and China Medical University, Taichung, 404, Taiwan.
- Division of Nephrology, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, No. 539, Zhong-Xiao Road, Chia-Yi, 600, Taiwan.
- Department of Nursing, Min-Hwei College of Health Care Management, Tainan, 736, Taiwan.
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14
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Kim KM, Jeon WJ, Kim EJ, Jang WG. CRTC2 suppresses BMP2-induced osteoblastic differentiation via Smurf1 expression in MC3T3-E1 cells. Life Sci 2018; 214:70-76. [PMID: 30449452 DOI: 10.1016/j.lfs.2018.10.052] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Revised: 10/18/2018] [Accepted: 10/25/2018] [Indexed: 12/14/2022]
Abstract
AIMS CREB (cAMP response element-binding protein)-regulated transcription coactivator (CRTC2) has been reported to act as a coactivator of CREB during gluconeogenesis. The role of CRTC2 in osteoblastic differentiation has not yet been elucidated. The aim of this study is to identify the mechanism of CRTC2 in osteoblast differentiation. MAIN METHODS The mRNA expression was determined by RT-PCR and qPCR. Protein levels were measured using Western blot assay. Alkaline phosphatase (ALP) staining was performed to evaluate ALP activity. Alizarin red S (ARS) staining was performed to measure extracellular mineralization. Transcriptional activity was detected using a luciferase assay. KEY FINDINGS In the present study, TNF-α was found to stimulate CRTC2 expression. However, TNF-α did not increase the gene expression of osteoblast differentiation markers and inhibited BMP2-induced osteoblastic differentiation. Overexpression of CRTC2 decreased the expression of osteogenic genes, ALP activity and extracellular matrix mineralization. Knockdown of CRTC2 restored BMP2-induced osteogenic gene expression and ALP activity. CRTC2 increased Smurf1 mRNA expression, Smurf 1 promoter activity, and protein level. Furthermore, Smurf 1 decreased Smad 1/5/9 protein levels. These results suggest that CRTC2 decreased BMP2-induced osteoblastic differentiation via Smurf 1 expression. SIGNIFICANCE Our results indicate that CRTC2 regulates the expression of Smurf1 in osteoblast differentiation.
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Affiliation(s)
- Kyeong-Min Kim
- Department of Biotechnology, School of Engineering, Daegu University, Gyeongbuk 38453, Republic of Korea; Research Institute of Anti-Aging, Daegu University, Gyeongbuk 38453, Republic of Korea
| | - Wan-Jin Jeon
- Department of Biotechnology, School of Engineering, Daegu University, Gyeongbuk 38453, Republic of Korea; Research Institute of Anti-Aging, Daegu University, Gyeongbuk 38453, Republic of Korea
| | - Eun-Jung Kim
- Research Institute of Anti-Aging, Daegu University, Gyeongbuk 38453, Republic of Korea; Department of Immunology, Kyungpook National University School of Medicine, Daegu 41944, Republic of Korea.
| | - Won-Gu Jang
- Department of Biotechnology, School of Engineering, Daegu University, Gyeongbuk 38453, Republic of Korea; Research Institute of Anti-Aging, Daegu University, Gyeongbuk 38453, Republic of Korea.
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15
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The Effect of Unfocused Extracorporeal Shock Wave Therapy on Bone Defect Healing in Diabetics. J Craniofac Surg 2018; 29:1081-1086. [DOI: 10.1097/scs.0000000000004303] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
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16
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Diedrich JD, Rajagurubandara E, Herroon MK, Mahapatra G, Hüttemann M, Podgorski I. Bone marrow adipocytes promote the Warburg phenotype in metastatic prostate tumors via HIF-1α activation. Oncotarget 2018; 7:64854-64877. [PMID: 27588494 PMCID: PMC5323121 DOI: 10.18632/oncotarget.11712] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Accepted: 08/21/2016] [Indexed: 12/21/2022] Open
Abstract
Metabolic adaptation is increasingly recognized as a key factor in tumor progression, yet its involvement in metastatic bone disease is not understood. Bone is as an adipocyte-rich organ, and a major site of metastasis from prostate cancer. Bone marrow adipocytes are metabolically active cells capable of shaping tumor metabolism via lipolysis and lipid transfer. In this study, using in vitro and in vivo models of marrow adiposity, we demonstrate that marrow fat cells promote Warburg phenotype in metastatic prostate cancer cells. We show increased expression of glycolytic enzymes, increased lactate production, and decreased mitochondrial oxidative phosphorylation in tumor cells exposed to adipocytes that require paracrine signaling between the two cell types. We also reveal that prostate cancer cells are capable of inducing adipocyte lipolysis as a postulated mechanism of sustenance. We provide evidence that adipocytes drive metabolic reprogramming of tumor cells via oxygen-independent mechanism of HIF-1α activation that can be reversed by HIF-1α downregulation. Importantly, we also demonstrate that the observed metabolic signature in tumor cells exposed to adipocytes mimics the expression patterns seen in patients with metastatic disease. Together, our data provide evidence for a functional relationship between marrow adipocytes and tumor cells in bone that has likely implications for tumor growth and survival within the metastatic niche.
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Affiliation(s)
- Jonathan D Diedrich
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA.,Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
| | | | - Mackenzie K Herroon
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Gargi Mahapatra
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA
| | - Maik Hüttemann
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA.,Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA
| | - Izabela Podgorski
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA.,Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
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17
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Ruppert K, Cauley J, Lian Y, Zgibor JC, Derby C, Solomon DH. The effect of insulin on bone mineral density among women with type 2 diabetes: a SWAN Pharmacoepidemiology study. Osteoporos Int 2018; 29:347-354. [PMID: 29075805 PMCID: PMC5818624 DOI: 10.1007/s00198-017-4276-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 10/13/2017] [Indexed: 12/12/2022]
Abstract
UNLABELLED This was a longitudinal study examining the effects of insulin use on bone mineral density loss. Insulin use was found to be associated with greater bone mineral density loss at the femoral neck among women with diabetes mellitus. INTRODUCTION Women with diabetes mellitus (DM) have higher bone mineral density (BMD) and experience slower BMD loss but have an increased risk of fracture. The data regarding the effect of insulin treatment on BMD remains conflicted. We examined the impact of insulin initiation on BMD. METHODS We investigated the annual changes in BMD associated with the new use of insulin among women with DM in the Study of Women's Health Across the Nation (SWAN). Propensity score (PS) matching, which is a statistical method that helps balance the baseline characteristics of women who did and did not initiate insulin, was used. Covariates with a potential impact on bone health were included in all models. Mixed model regression was used to test the change in BMD between the two groups. Median follow-up time was 5.4 years. RESULTS The cohort consisted of 110 women, mean age, 53.6 years; 49% white and 51% black. Women using insulin (n = 55) were similar on most relevant characteristics to the 55 not using insulin. Median diabetes duration for the user group was 10 vs. 5.0 years for the non-user group. There was a greater loss of BMD at the femoral neck among insulin users (- 1.1%) vs non-users (- 0.77%) (p = 0.04). There were no differences in BMD loss at the spine - 0.30% vs - 0.32% (p = 0.85) or at the total hip - 0.31% vs - 0.25 (p = 0.71), respectively. CONCLUSIONS Women with T2DM who initiated insulin experienced a more rapid BMD loss at the femoral neck as compared to women who did use insulin.
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Affiliation(s)
- K Ruppert
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 4420 Bayard St Suite 600, Pittsburgh, PA, 15260, USA.
| | - J Cauley
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 4420 Bayard St Suite 600, Pittsburgh, PA, 15260, USA
| | - Y Lian
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 4420 Bayard St Suite 600, Pittsburgh, PA, 15260, USA
| | - J C Zgibor
- Department of Epidemiology and Biostatistics, University of South Florida, Tampa, FL, USA
| | - C Derby
- Department of Neurology, Albert Einstein College of Medicine, New York, NY, USA
| | - D H Solomon
- Division of Rheumatology, Division of Pharmacoepidemiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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18
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Xiong Y, Zhang Y, Xin N, Yuan Y, Zhang Q, Gong P, Wu Y. 1α,25-Dihydroxyvitamin D 3 promotes bone formation by promoting nuclear exclusion of the FoxO1 transcription factor in diabetic mice. J Biol Chem 2017; 292:20270-20280. [PMID: 29042442 PMCID: PMC5724012 DOI: 10.1074/jbc.m117.796367] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 09/27/2017] [Indexed: 02/05/2023] Open
Abstract
1α,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is the active form of vitamin D, which is responsible for reducing the risk for diabetes mellitus (DM), decreasing insulin resistance, and improving insulin secretion. Previous studies have shown that 1,25(OH)2D3 inhibited the activity of FoxO1, which has been implicated in the regulation of glucose metabolism. However, its function and mechanism of action in DM-induced energy disorders and also in bone development remains unclear. Here, using in vitro and in vivo approaches including osteoblast-specific, conditional FoxO1-knock-out mice, we demonstrate that 1,25(OH)2D3 ameliorates abnormal osteoblast proliferation in DM-induced oxidative stress conditions and rescues the impaired glucose and bone metabolism through FoxO1 nuclear exclusion resulting from the activation of PI3K/Akt signaling. Using alizarin red staining, alkaline phosphatase assay, Western blot, and real-time qPCR techniques, we found that 1,25(OH)2D3 promotes osteoblast differentiation and expression of osteogenic phenotypic markers (i.e. alkaline phosphatase (1), collagen 1 (COL-1), osteocalcin (OCN), and osteopontin (OPN)) in a high-glucose environment. Moreover, 1,25(OH)2D3 increased both total OCN secretion and levels of uncarboxylated OCN (GluOC) by phosphorylating FoxO1 and promoting its nuclear exclusion, indicated by Western blot and cell immunofluorescence analyses. Taken together, our findings confirm that FoxO1 is a key mediator involved in glucose homeostasis and indicate that 1,25(OH)2D3 improves glucose metabolism and bone development via regulation of PI3K/Akt/FoxO1/OCN pathway.
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Affiliation(s)
- Yi Xiong
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chengdu 610041, China; Department of Implantology, Chengdu 610041, China
| | - Yixin Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chengdu 610041, China; Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Na Xin
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chengdu 610041, China; Department of Implantology, Chengdu 610041, China
| | - Ying Yuan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chengdu 610041, China; Department of Implantology, Chengdu 610041, China
| | - Qin Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chengdu 610041, China; Department of Implantology, Chengdu 610041, China
| | - Ping Gong
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chengdu 610041, China; Department of Implantology, Chengdu 610041, China.
| | - Yingying Wu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chengdu 610041, China; Department of Implantology, Chengdu 610041, China.
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19
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Bacevic M, Brkovic B, Albert A, Rompen E, Radermecker RP, Lambert F. Does Oxidative Stress Play a Role in Altered Characteristics of Diabetic Bone? A Systematic Review. Calcif Tissue Int 2017; 101:553-563. [PMID: 29063963 DOI: 10.1007/s00223-017-0327-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 09/12/2017] [Indexed: 01/22/2023]
Abstract
Diabetes mellitus (DM) has been associated with increased bone fracture rates, impaired bone regeneration, delayed bone healing, and depressed osteogenesis. However, the plausible pathogenic mechanisms remain incompletely understood. The aim of the present systematic review was to investigate whether oxidative stress (OS) plays a role in altered characteristics of diabetic bone under in vivo conditions. An electronic search of the MEDLINE (via PubMed) and Embase databases was performed. In vivo animal studies involving DM and providing information regarding assessment of OS markers combined with analyses of bone histology/histomorphometry parameters were selected. A descriptive analysis of selected articles was performed. Ten studies were included in the present review. Both bone formation and bone resorption parameters were significantly decreased in the diabetic groups of animals compared to the healthy groups. This finding was consistent regardless of different animal/bone models employed or different evaluation periods. A statistically significant increase in systemic and/or local OS status was also emphasised in the diabetic groups in comparison to the healthy ones. Markers of OS were associated with histological and/or histomorphometric parameters, including decreased trabecular bone and osteoid volumes, suppressed bone formation, defective bone mineralisation, and reduced osteoclastic activity, in diabetic animals. Additionally, insulin and antioxidative treatment proved to be efficient in reversing the deleterious effects of high glucose and associated OS. The present findings support the hypotheses that OS in the diabetic condition contributes at least partially to defective bone features, and that antioxidative supplementation can be a valuable adjunctive strategy in treating diabetic bone disease, accelerating bone healing, and improving osteointegration.
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Affiliation(s)
- Miljana Bacevic
- Dental Biomaterials Research Unit (d-BRU), Faculty of Medicine, University of Liege, Liège, Belgium
- Clinic of Oral Surgery, School of Dental Medicine, University of Belgrade, Belgrade, Serbia
| | - Bozidar Brkovic
- Clinic of Oral Surgery, School of Dental Medicine, University of Belgrade, Belgrade, Serbia
| | - Adelin Albert
- Department of Biostatistics, University Hospital of Liege, Liège, Belgium
| | - Eric Rompen
- Department of Periodontology and Oral Surgery, Faculty of Medicine, University of Liege, Liège, Belgium
| | - Regis P Radermecker
- Department of Diabetes, Nutrition and Metabolic Disorders, University Hospital of Liege, Liège, Belgium
| | - France Lambert
- Dental Biomaterials Research Unit (d-BRU), Faculty of Medicine, University of Liege, Liège, Belgium.
- Department of Periodontology and Oral Surgery, Faculty of Medicine, University of Liege, Liège, Belgium.
- Service de Médecine Dentaire, Domaine du Sart Tilman Bat B-35, 4000, Liège, Belgium.
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20
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Sheu Y, Amati F, Schwartz AV, Danielson ME, Li X, Boudreau R, Cauley JA. Vertebral bone marrow fat, bone mineral density and diabetes: The Osteoporotic Fractures in Men (MrOS) study. Bone 2017; 97:299-305. [PMID: 28179169 PMCID: PMC5367972 DOI: 10.1016/j.bone.2017.02.001] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 12/22/2016] [Accepted: 02/01/2017] [Indexed: 01/27/2023]
Abstract
Elevated vertebral bone marrow fat (BMF) among individuals with osteoporosis has been established in histomorphometric studies. Several studies have found a negative correlation between BMF and bone mineral density (BMD) at the spine in men and women across different age groups. Animal studies have also observed bone loss with increased BMF in mice with induced diabetes. Our study objective was to test the hypothesis that the association between BMF and BMD varies by diabetic status. We performed a cross-sectional study of 156 men aged 74-96years from the Osteoporotic Fractures in Men study at the Pittsburgh clinical site. All men had spine BMF scans using proton magnetic resonance spectroscopy and spine and hip BMD scans by dual-energy X-ray absorptiometry. BMF was expressed as lipid to "lipid+water" ratio (%). Men were considered diabetic if they self-reported a physician diagnosis of diabetes, diabetes medication or had a fasting glucose ≥126mg/dl. Men with diabetes (n=38) had a significantly higher spine BMF (58.9 vs. 54.6%, p=0.0035), spine BMD (1.20 vs. 1.10g/cm2, P=0.007) and total hip BMD (1.00 vs. 0.94g/cm2, p=0.04) than those without, while no differences were observed for body weight, body mass index or waist circumference. Pearson correlation tests showed no significant correlation of spine BMF with age or BMD in non-diabetics. Significant inverse correlations were observed between BMF and BMD (-0.30 for femoral neck and -0.39 for total hip) among diabetic men. In conclusion, men with diabetes had a higher BMF compared to non-diabetic men. The correlation between BMF and BMD differed by diabetes status. Further investigation of the association of diabetes with BMF and BMD may provide a better understanding of the high fracture rates among individuals with diabetes despite their higher BMD.
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Affiliation(s)
- Yahtyng Sheu
- Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Francesca Amati
- Department of Physiology, University of Lausanne, Lausanne, Switzerland; Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, PA, USA.
| | - Ann V Schwartz
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.
| | | | - Xiaojuan Li
- School of Medicine, University of California, San Francisco, San Francisco, CA, USA.
| | - Robert Boudreau
- Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jane A Cauley
- Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA; School of Medicine, University of California, San Francisco, San Francisco, CA, USA.
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21
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Cutruzzolà F, Giardina G, Marani M, Macone A, Paiardini A, Rinaldo S, Paone A. Glucose Metabolism in the Progression of Prostate Cancer. Front Physiol 2017; 8:97. [PMID: 28270771 PMCID: PMC5318430 DOI: 10.3389/fphys.2017.00097] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 02/06/2017] [Indexed: 01/23/2023] Open
Abstract
Prostate cancer is one of the most common types of cancer in western country males but the mechanisms involved in the transformation processes have not been clearly elucidated. Alteration in cellular metabolism in cancer cells is recognized as a hallmark of malignant transformation, although it is becoming clear that the biological features of metabolic reprogramming not only differ in different cancers, but also among different cells in a type of cancer. Normal prostate epithelial cells have a peculiar and very inefficient energy metabolism as they use glucose to synthesize citrate that is secreted as part of the seminal liquid. During the transformation process, prostate cancer cells modify their energy metabolism from inefficient to highly efficient, often taking advantage of the interaction with other cell types in the tumor microenvironment that are corrupted to produce and secrete metabolic intermediates used by cancer cells in catabolic and anabolic processes. We recapitulate the metabolic transformations occurring in the prostate from the normal cell to the metastasis, highlighting the role of the microenvironment and summarizing what is known on the molecular mechanisms involved in the process.
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Affiliation(s)
- Francesca Cutruzzolà
- Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome Rome, Italy
| | - Giorgio Giardina
- Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome Rome, Italy
| | - Marina Marani
- Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome Rome, Italy
| | - Alberto Macone
- Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome Rome, Italy
| | - Alessandro Paiardini
- Department of Biology and Biotechnology "Charles Darwin", Sapienza Università di Roma Rome, Italy
| | - Serena Rinaldo
- Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome Rome, Italy
| | - Alessio Paone
- Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome Rome, Italy
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22
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Sanchez-Enriquez S, Ballesteros-Gonzalez IT, Villafán-Bernal JR, Pascoe-Gonzalez S, Rivera-Leon EA, Bastidas-Ramirez BE, Rivas-Carrillo JD, Alcala-Zermeno JL, Armendariz-Borunda J, Llamas-Covarrubias IM, Zepeda-Moreno A. Serum levels of undercarboxylated osteocalcin are related to cardiovascular risk factors in patients with type 2 diabetes mellitus and healthy subjects. World J Diabetes 2017; 8:11-17. [PMID: 28138360 PMCID: PMC5237813 DOI: 10.4239/wjd.v8.i1.11] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2016] [Revised: 10/06/2016] [Accepted: 11/17/2016] [Indexed: 02/05/2023] Open
Abstract
AIM To determine a potential relationship between serum undercarboxylated (ucOC) concentration and cardiovascular risk factors in type 2 diabetes (T2D) patients and healthy subjects (HS).
METHODS A cross-sectional study was conducted on 140 subjects classified into two groups, 70 with T2D and 70 HS. Medical history and physical examination with anthropometric measurements were obtained from all subjects. Body fat percentage was determined by bioelectrical impendency analysis. Serum ucOC concentration was determined by enzyme immunoassay, while serum levels of insulin and hsCRP were obtained using high sensitivity enzyme-linked immunosorbent assay. Insulin resistance was determined using the homeostasis model assessment-IR. Lipid profile [triglycerides, total cholesterol (TC), high-density lipoproteins (HDL-c), low density lipoproteins (LDL-c), very low-density lipoproteins] was determined by spectrophotometry and standard formulas when applicable.
RESULTS The T2D patient group showed significantly higher values of waist circumference, waist-to-hip ratio, systolic blood pressure (SBP), diastolic blood pressure (DBP), current smoking, and alcohol use when compared to the HS group (P < 0.05). We observed a significantly lower serum ucOC concentration in T2D than in HS (1.5 ± 1.4 vs 2.3 ± 1.8, P < 0.05). In the whole study population, ucOC concentration was inversely correlated with body mass index (BMI) (r = -0.236, P < 0.05), fasting plasma glucose (r = -0.283, P < 0.01) and HDL-c (r = -0.255, P < 0.05); and positively correlated with LDL-c/HDL-c ratio (r = 0.306, P < 0.05) and TC/HDL-c ratio (r = 0.284, P < 0.05). In the T2D group, serum ucOC concentration was inversely correlated with BMI (r = -0.310, P < 0.05) and body-fat percentage (r = -0.311, P < 0.05), and positively correlated with DBP (r = 0.450, P < 0.01). In HS group a positive correlation between serum levels of ucOC and SBP (r = 0.277, P < 0.05) was observed.
CONCLUSION Serum ucOC is a potential marker for cardiovascular risk in Mexicans because it is related to adiposity parameters, blood pressure and lipid profile.
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23
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Tsentidis C, Gourgiotis D, Kossiva L, Doulgeraki A, Marmarinos A, Galli-Tsinopoulou A, Karavanaki K. Higher levels of s-RANKL and osteoprotegerin in children and adolescents with type 1 diabetes mellitus may indicate increased osteoclast signaling and predisposition to lower bone mass: a multivariate cross-sectional analysis. Osteoporos Int 2016; 27:1631-1643. [PMID: 26588909 DOI: 10.1007/s00198-015-3422-5] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Accepted: 11/10/2015] [Indexed: 12/20/2022]
Abstract
UNLABELLED Simultaneous lower bone mineral density, metabolic bone markers, parathyroid hormone (PTH), magnesium, insulin-like growth factor 1 (IGF1), and higher levels of total soluble receptor activator of nuclear factor-kappa B ligand (s-RANKL), osteoprotegerin (OPG), and alkaline phosphatase (ALP) are indicative of lower osteoblast and increased osteoclast signaling in children and adolescents with type 1 diabetes mellitus, predisposing to adult osteopenia and osteoporosis. INTRODUCTION Type 1 diabetes mellitus (T1DM) is a risk factor for reduced bone mass, disrupting several bone metabolic pathways. We aimed at identifying association patterns between bone metabolic markers, particularly OPG, s-RANKL, and bone mineral density (BMD) in T1DM children and adolescents, in order to study possible underlying pathophysiologic mechanisms of bone loss. METHODS We evaluated 40 children and adolescents with T1DM (mean ± SD age 13.04 ± 3.53 years, T1DM duration 5.15 ± 3.33 years) and 40 healthy age- and gender-matched controls (aged12.99 ± 3.3 years). OPG, s-RANKL, osteocalcin, C-telopeptide cross-links (CTX), IGF1, electrolytes, PTH, and total 25(OH)D were measured, and total body along with lumbar spine BMD were evaluated with dual energy X-ray absorptiometry (DXA). Multivariate regression and factor analysis were performed after classic inference. RESULTS Patients had significantly lower BMD, with lower bone turnover markers, PTH, magnesium, and IGF1 than controls, indicating lower osteoblast signaling. Higher levels of total s-RANKL, OPG, and total ALP were observed in patients, with log(s-RANKL) and OPG correlation found only in controls, possibly indicating increased osteoclast signaling in patients. Coupling of bone resorption and formation was observed in both groups. Multivariate regression confirmed simultaneous lower bone turnover, IGF1, magnesium, and higher total s-RANKL, OPG, and ALP in patients, while factor analysis indicated possible activation of RANK/RANKL/OPG system in patients and its association with magnesium and IGF1. Patients with longer disease duration or worse metabolic control had lower BMD. CONCLUSIONS T1DM children and adolescents have impaired bone metabolism which seems to be multifactorial. Reduced osteoblast and increased osteoclast signaling, resulting from multiple simultaneous disturbances, could lead to reduced peak bone accrual in early adulthood, predisposing to adult osteopenia and osteoporosis.
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Affiliation(s)
- C Tsentidis
- Diabetes Clinic, 2nd Department of Pediatrics, Athens University Medical School, "P&A Kyriakou" Children's Hospital, Thivon & Livadias, 11527, Ampelokipi, Athens, Greece.
| | - D Gourgiotis
- Laboratory of Clinical Biochemistry-Molecular Diagnostics, 2nd Department of Pediatrics, Athens University Medical School, "P&A Kyriakou" Children's Hospital, Athens, Greece
| | - L Kossiva
- Diabetes Clinic, 2nd Department of Pediatrics, Athens University Medical School, "P&A Kyriakou" Children's Hospital, Thivon & Livadias, 11527, Ampelokipi, Athens, Greece
| | - A Doulgeraki
- Department of Bone and Mineral Metabolism, Institute of Child Health, "Aghia Sophia" Children's Hospital, Athens, Greece
| | - A Marmarinos
- Laboratory of Clinical Biochemistry-Molecular Diagnostics, 2nd Department of Pediatrics, Athens University Medical School, "P&A Kyriakou" Children's Hospital, Athens, Greece
| | - A Galli-Tsinopoulou
- Fourth Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Thessaloniki, Greece
| | - K Karavanaki
- Diabetes Clinic, 2nd Department of Pediatrics, Athens University Medical School, "P&A Kyriakou" Children's Hospital, Thivon & Livadias, 11527, Ampelokipi, Athens, Greece
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Mansur SA, Mieczkowska A, Bouvard B, Flatt PR, Chappard D, Irwin N, Mabilleau G. Stable Incretin Mimetics Counter Rapid Deterioration of Bone Quality in Type 1 Diabetes Mellitus. J Cell Physiol 2015; 230:3009-18. [PMID: 26016732 DOI: 10.1002/jcp.25033] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 05/04/2015] [Indexed: 01/13/2023]
Abstract
Type 1 diabetes mellitus is associated with a high risk for bone fractures. Although bone mass is reduced, bone quality is also dramatically altered in this disorder. However, recent evidences suggest a beneficial effect of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) pathways on bone quality. The aims of the present study were to conduct a comprehensive investigation of bone strength at the organ and tissue level; and to ascertain whether enzyme resistant GIP or GLP-1 mimetic could be beneficial in preventing bone fragility in type 1 diabetes mellitus. Streptozotocin-treated mice were used as a model of type 1 diabetes mellitus. Control and streptozotocin-diabetic animals were treated for 21 days with an enzymatic-resistant GIP peptide ([D-Ala(2) ]GIP) or with liraglutide (each at 25 nmol/kg bw, ip). Bone quality was assessed at the organ and tissue level by microCT, qXRI, 3-point bending, qBEI, nanoindentation, and Fourier-transform infrared microspectroscopy. [D-Ala2]GIP and liraglutide treatment did prevent loss of whole bone strength and cortical microstructure in the STZ-injected mice. However, tissue material properties were significantly improved in STZ-injected animals following treatment with [D-Ala2]GIP or liraglutide. Treatment of STZ-diabetic mice with [D-Ala(2) ]GIP or liraglutide was capable of significantly preventing deterioration of the quality of the bone matrix. Further studies are required to further elucidate the molecular mechanisms involved and to validate whether these findings can be translated to human patients.
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Affiliation(s)
- Sity Aishah Mansur
- School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom.,University Tun Hussein Onn Malaysia, Johor, Malaysia
| | | | - Béatrice Bouvard
- GEROM-LHEA, Institut de Biologie en Santé, LUNAM Université, Angers, France
| | - Peter R Flatt
- School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom
| | - Daniel Chappard
- GEROM-LHEA, Institut de Biologie en Santé, LUNAM Université, Angers, France.,SCIAM, Institut de Biologie en Santé, LUNAM Université, Angers, France
| | - Nigel Irwin
- School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom
| | - Guillaume Mabilleau
- GEROM-LHEA, Institut de Biologie en Santé, LUNAM Université, Angers, France.,SCIAM, Institut de Biologie en Santé, LUNAM Université, Angers, France
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25
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Diedrich J, Gusky HC, Podgorski I. Adipose tissue dysfunction and its effects on tumor metabolism. Horm Mol Biol Clin Investig 2015; 21:17-41. [PMID: 25781550 DOI: 10.1515/hmbci-2014-0045] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 01/14/2015] [Indexed: 12/12/2022]
Abstract
Growing by an alarming rate in the Western world, obesity has become a condition associated with a multitude of diseases such as diabetes, metabolic syndrome and various cancers. Generally viewed as an abnormal accumulation of hypertrophied adipocytes, obesity is also a poor prognostic factor for recurrence and chemoresistance in cancer patients. With more than two-thirds of the adult population in the United States considered clinically overweight or obese, it is critical that the relationship between obesity and cancer is further emphasized and elucidated. Adipocytes are highly metabolically active cells, which, through release of adipokines and cytokines and activation of endocrine and paracrine pathways, affect processes in neighboring and distant cells, altering their normal homeostasis. This work will examine specifically how adipocyte-derived factors regulate the cellular metabolism of malignant cells within the tumor niche. Briefly, tumor cells undergo metabolic pressure towards a more glycolytic and hypoxic state through a variety of metabolic regulators and signaling pathways, i.e., phosphoinositol-3 kinase (PI3K), hypoxia-inducible factor-1 alpha (HIF-1α), and c-MYC signaling. Enhanced glycolysis and high lactate production are hallmarks of tumor progression largely because of a process known as the Warburg effect. Herein, we review the latest literature pertaining to the body of work on the interactions between adipose and tumor cells, and underlining the changes in cancer cell metabolism that have been targeted by the currently available treatments.
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26
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Mieczkowska A, Mansur SA, Irwin N, Flatt PR, Chappard D, Mabilleau G. Alteration of the bone tissue material properties in type 1 diabetes mellitus: A Fourier transform infrared microspectroscopy study. Bone 2015; 76:31-9. [PMID: 25813583 DOI: 10.1016/j.bone.2015.03.010] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Revised: 02/23/2015] [Accepted: 03/12/2015] [Indexed: 10/23/2022]
Abstract
Type 1 diabetes mellitus (T1DM) is a severe disorder characterized by hyperglycemia and hypoinsulinemia. A higher occurrence of bone fractures has been reported in T1DM, and although bone mineral density is reduced in this disorder, it is also thought that bone quality may be altered in this chronic pathology. Vibrational microscopies such as Fourier transform infrared microspectroscopy (FTIRM) represent an interesting approach to study bone quality as they allow investigation of the collagen and mineral compartment of the extracellular matrix in a specific bone location. However, as spectral feature arising from the mineral may overlap with those of the organic component, the demineralization of bone sections should be performed for a full investigation of the organic matrix. The aims of the present study were to (i) develop a new approach, based on the demineralization of thin bone tissue section to allow a better characterization of the bone organic component by FTIRM, (ii) to validate collagen glycation and collagen integrity in bone tissue and (iii) to better understand what alterations of tissue material properties in newly forming bone occur in T1DM. The streptozotocin-injected mouse (150 mg/kg body weight, injected at 8 weeks old) was used as T1DM model. Animals were randomly allocated to control (n = 8) or diabetic (n = 10) groups and were sacrificed 4 weeks post-STZ injection. Bones were collected at necropsy, embedded in polymethylmethacrylate and sectioned prior to examination by FTIRM. FTIRM collagen parameters were collagen maturity (area ratio between 1660 and 1690 cm(-1) subbands), collagen glycation (area ratio between the 1032 cm(-1) subband and amide I) and collagen integrity (area ratio between the 1338 cm(-1) subband and amide II). No significant differences in the mineral compartment of the bone matrix could be observed between controls and STZ-injected animals. On the other hand, as compared with controls, STZ-injected animals presented with significant higher value for collagen maturity (17%, p = 0.0048) and collagen glycation (99%, p = 0.0121), while collagen integrity was significantly lower by 170% (p = 0.0121). This study demonstrated the profound effect of early T1DM on the organic compartment of the bone matrix in newly forming bone. Further studies in humans are required to ascertain whether T1DM also lead to similar effect on the quality of the bone matrix.
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Affiliation(s)
| | - Sity Aishah Mansur
- School of Biomedical Sciences, University of Ulster, Coleraine, United Kingdom; University Tun Hussein Onn Malaysia, Johor, Malaysia
| | - Nigel Irwin
- School of Biomedical Sciences, University of Ulster, Coleraine, United Kingdom
| | - Peter R Flatt
- School of Biomedical Sciences, University of Ulster, Coleraine, United Kingdom
| | - Daniel Chappard
- LUNAM Université, GEROM-LHEA, Institut de Biologie en Santé, Angers, France; LUNAM Université, SCIAM, Institut de Biologie en Santé, Angers, France
| | - Guillaume Mabilleau
- LUNAM Université, GEROM-LHEA, Institut de Biologie en Santé, Angers, France; LUNAM Université, SCIAM, Institut de Biologie en Santé, Angers, France.
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Sheu Y, Bunker CH, Jonnalagadda P, Cvejkus RK, Patrick AL, Wheeler VW, Gordon CL, Zmuda JM. Rates of and risk factors for trabecular and cortical BMD loss in middle-aged and elderly African-ancestry men. J Bone Miner Res 2015; 30:543-53. [PMID: 25213918 PMCID: PMC4878409 DOI: 10.1002/jbmr.2359] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Revised: 09/08/2014] [Accepted: 09/08/2014] [Indexed: 11/11/2022]
Abstract
Low trabecular (Tb) and cortical (Ct) volumetric BMD (vBMD) are related to increased fracture risk, but little is known about the patterns and correlates of Tb and Ct vBMD loss with aging. We examined the rates of change in total, Tb.vBMD, and Ct.vBMD at the radius and tibia, and identified factors associated with vBMD loss among 1569 men of African descent aged 40 years and older. Quantitative computed tomography was used to measure vBMD 6 years apart. The annualized rate of loss in Tb.vBMD was significant at the radius (-0.047%/yr, p = 0.016) but not at the tibia. At the radius, a significant loss of Tb.vBMD was observed in men aged 40 to 49 years that appeared to be attenuated and not statistically significant among older age men. In contrast, the decline in Ct.vBMD was similar at both skeletal sites (-0.254 to -0.264%/yr, p < 0.0001) and was consistent across all age groups. Positive associations were found for vBMD changes with body weight (all but radius Ct.vBMD) and diabetes (Ct.vBMD only), whereas negative associations were found with hypertension (all but radius Tb.vBMD), smoking (Ct.vBMD only), and androgen deprivation therapy (cortical vBMD only). Trabecular and cortical vBMD loss appears to follow different patterns among middle- and older-aged men of African ancestry. Factors associated with the decline in vBMD also varied by compartment and anatomical site. Additional studies are needed to better understand the physiological mechanisms underlying early BMD loss among African-ancestry men.
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Affiliation(s)
- Yahtyng Sheu
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
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DXA variations and fractures after simultaneous pancreas-renal transplantation: results of a long-term follow-up. Clin Nucl Med 2014; 40:e232-5. [PMID: 25525928 DOI: 10.1097/rlu.0000000000000643] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Simultaneous pancreas-kidney transplant (SPKT) has been associated with an increased risk of fracture. We prospectively evaluated the long-term effects of SPKT on bone mineral density (BMD) and fracture risk. During 1998 to 1999, 29 participants were consecutively monitored, and 18 completed the 10-year follow-up. Laboratory blood parameters, lumbar-dorsal radiography, and DEXA were determined at baseline, 1 year, and 10 years. The medical record was reviewed for peripheral fragility fractures. The BMD revealed no changes between baseline and 1 or 10 years after SPKT. Lumbar-dorsal radiography showed 0% asymptomatic vertebral fractures at baseline and after 1 year with 16.7% at 10 years. Vertebral asymptomatic fractures were correlated with acute rejection episodes (P = 0.025). During the first year, no nonvertebral fractures were identified. At the end of the follow-up, 5 nonvertebral fractures in 4 patients were reported. Dorsal and lumbar spine fractures correlated with lumbar spine t score (r = -0.591, P =0.022) and peripheral fractures with femoral neck t score (r = -0.633, P = 0.013). Patients with SPKT did not show long-term significant loss of BMD. The incidence of vertebral fractures was low and related to steroid treatment; the incidence of peripheral fractures was higher and independent of clinical or biochemical parameters.
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29
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Abstract
Incidence of skeletal metastases and death from prostate cancer greatly increases with age and obesity, conditions which increase marrow adiposity. Bone marrow adipocytes are metabolically active components of bone metastatic niche that modulate the function of neighboring cells; yet the mechanisms of their involvement in tumor behavior in bone have not been explored. In this study, using experimental models of intraosseous tumor growth and diet-induced obesity, we demonstrate the promoting effects of marrow fat on growth and progression of skeletal prostate tumors. We reveal that exposure to lipids supplied by marrow adipocytes induces expression of lipid chaperone FABP4, pro-inflammatory interleukin IL-1β, and oxidative stress protein HMOX-1 in metastatic tumor cells and stimulates their growth and invasiveness. We show that FABP4 is highly overexpressed in prostate skeletal tumors from obese mice and in bone metastasis samples from prostate cancer patients. In addition, we provide results suggestive of bi-directional interaction between FABP4 and PPARγ pathways that may be driving aggressive tumor cell behavior in bone. Together, our data provide evidence for functional relationship between bone marrow adiposity and metastatic prostate cancers and unravel the FABP4/IL-1β axis as a potential therapeutic target for this presently incurable disease.
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Joshi AS, Varthakavi PK, Bhagwat NM, Chadha MD. Response to review article "Type 1 diabetes and osteoporosis: Review of literature". Indian J Endocrinol Metab 2014; 18:589-590. [PMID: 25143926 PMCID: PMC4138925 DOI: 10.4103/2230-8210.137505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Affiliation(s)
- Ameya S. Joshi
- Department of Endocrinology, Topiwala National Medical College and BYL Nair Charitable Hospital, Mumbai Central, Mumbai, Maharashtra, India
| | - Premlata K. Varthakavi
- Department of Endocrinology, Topiwala National Medical College and BYL Nair Charitable Hospital, Mumbai Central, Mumbai, Maharashtra, India
| | - Nikhil M. Bhagwat
- Department of Endocrinology, Topiwala National Medical College and BYL Nair Charitable Hospital, Mumbai Central, Mumbai, Maharashtra, India
| | - Manoj D. Chadha
- Department of Endocrinology, Topiwala National Medical College and BYL Nair Charitable Hospital, Mumbai Central, Mumbai, Maharashtra, India
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Abstract
The complexity of cell interactions with their microenvironment and their ability to communicate at the autocrine, paracrine, and endocrine levels has gradually but significantly evolved in the last three decades. The musculoskeletal system has been historically recognized to be governed by a relationship of proximity and function, chiefly dictated by mechanical forces and the work of gravity itself. In this review article, we first provide a historical overview of the biomechanical theory of bone- muscle interactions. Next, we expand to detail the significant evolution in our understanding of the function of bones and muscles as secretory organs. Then, we review and discuss new evidence in support of a biochemical interaction between these two tissues. We then propose that these two models of interaction are complementary and intertwined providing for a new frontier for the investigation of how bone-muscle cross talk could be fully explored for the targeting of new therapies for musculoskeletal diseases, particularly the twin conditions of aging, osteoporosis and sarcopenia. In the last section, we explore the bone-muscle cross talk in the context of their interactions with other tissues and the global impact of these multi-tissue interactions on chronic diseases.
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Affiliation(s)
- Janalee Isaacson
- Muscle Biology Research Group-MUBIG, School of Nursing and Health Studies, University of Missouri-Kansas City (UMKC), 2464 Charlotte St, Kansas City, MO 64108, USA; Nursing Program, Johnson County Community College, Overland Park, KS 66210, USA
| | - Marco Brotto
- Muscle Biology Research Group-MUBIG, School of Nursing and Health Studies, University of Missouri-Kansas City (UMKC), 2464 Charlotte St, Kansas City, MO 64108, USA; School of Medicine, UMKC, Kansas City, MO, USA; School of Pharmacy, UMKC, Kansas City, MO, USA
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Srikanthan P, Crandall CJ, Miller-Martinez D, Seeman TE, Greendale GA, Binkley N, Karlamangla AS. Insulin resistance and bone strength: findings from the study of midlife in the United States. J Bone Miner Res 2014; 29:796-803. [PMID: 23983216 PMCID: PMC3935990 DOI: 10.1002/jbmr.2083] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2013] [Revised: 07/30/2013] [Accepted: 08/13/2013] [Indexed: 12/11/2022]
Abstract
Although several studies have noted increased fracture risk in individuals with type 2 diabetes mellitus (T2DM), the pathophysiologic mechanisms underlying this association are not known. We hypothesize that insulin resistance (the key pathology in T2DM) negatively influences bone remodeling and leads to reduced bone strength. Data for this study came from 717 participants in the Biomarker Project of the Midlife in the United States Study (MIDUS II). The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated from fasting morning blood glucose and insulin levels. Projected 2D (areal) bone mineral density (BMD) was measured in the lumbar spine and left hip using dual-energy X-ray absorptiometry (DXA). Femoral neck axis length and width were measured from the hip DXA scans, and combined with BMD and body weight and height to create composite indices of femoral neck strength relative to load in three different failure modes: compression, bending, and impact. We used multiple linear regressions to examine the relationship between HOMA-IR and bone strength, adjusted for age, gender, race/ethnicity, menopausal transition stage (in women), and study site. Greater HOMA-IR was associated with lower values of all three composite indices of femoral neck strength relative to load, but was not associated with BMD in the femoral neck. Every doubling of HOMA-IR was associated with a 0.34 to 0.40 SD decrement in the strength indices (p<0.001). On their own, higher levels of fasting insulin (but not of glucose) were independently associated with lower bone strength. Our study confirms that greater insulin resistance is related to lower femoral neck strength relative to load. Further, we note that hyperinsulinemia, rather than hyperglycemia, underlies this relationship. Although cross-sectional associations do not prove causality, our findings do suggest that insulin resistance and in particular, hyperinsulinemia, may negatively affect bone strength relative to load.
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Affiliation(s)
- Preethi Srikanthan
- Department of Medicine David Geffen School of Medicine at UCLA Los Angeles, California, USA
| | - Carolyn J. Crandall
- Department of Medicine David Geffen School of Medicine at UCLA Los Angeles, California, USA
| | - Dana Miller-Martinez
- Department of Medicine David Geffen School of Medicine at UCLA Los Angeles, California, USA
| | - Teresa E. Seeman
- Department of Medicine David Geffen School of Medicine at UCLA Los Angeles, California, USA
| | - Gail A. Greendale
- Department of Medicine David Geffen School of Medicine at UCLA Los Angeles, California, USA
| | - Neil Binkley
- Osteoporosis Clinical Center Univ of Wisconsin-Madison, Madison, WI
| | - Arun S. Karlamangla
- Department of Medicine David Geffen School of Medicine at UCLA Los Angeles, California, USA
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Xing D, Ma XL, Ma JX, Wang J, Yang Y, Chen Y. Association between use of benzodiazepines and risk of fractures: a meta-analysis. Osteoporos Int 2014; 25:105-20. [PMID: 24013517 DOI: 10.1007/s00198-013-2446-y] [Citation(s) in RCA: 90] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2013] [Accepted: 06/14/2013] [Indexed: 01/11/2023]
Abstract
UNLABELLED Benzodiazepines (BZDs) are some of the most commonly prescribed drugs in the world. It has been shown that BZD use could be associated with increased fracture risk. However, studies on the use of BZDs and fracture risk have yielded inconsistent results. Results from the present meta-analysis show that BZD use is associated with a moderate and clinically significant increase in the risk of fractures. INTRODUCTION The relationship between the use of BZDs and fracture risk has been neither well identified nor summarized. This meta-analysis reports on the use of BZDs, especially short-acting BZDs, and their correlation with a moderate and clinically significant increase in fracture risk. This analysis will provide evidence for clinicians to consider fracture risk when prescribing BZDs among the elderly population. This study was conducted to determine whether people who take BZDs are at an increased fracture risk. METHODS A systematic search of studies published through January 2013 was conducted using MEDLINE, EMBASE, OVID, and ScienceDirect. Case-control and cohort studies that assessed the relationship between BZD use and the risk of fractures were identified. Literature searches, study selections, methodological assessments, and data mining were independently conducted by two reviewers. Disagreements were resolved by consensus. STATA 12.0 software was used for the meta-analysis. Random effects models were used for pooled analysis due to heterogeneity among the studies. RESULTS There were 25 studies, including 19 case-control studies and 6 cohort studies, that met the inclusion criteria. Overall, the results of the meta-analysis indicated that BZD use was associated with a significantly increased fracture risk (relative risk (RR) = 1.25; 95% confidence intervals (CI), 1.17-1.34; p < 0.001). Increased fracture risk associated with BZD use was observed in participants aged ≥65 years old (RR = 1.26; 95% CI, 1.15-1.38; p < 0.001). When only hip fractures were included as the outcome measure, the RR increased to 1.35. However, subgroup meta-analyses showed that there was no significant association between BZD use and fracture risk in Eastern countries (RR = 1.27; 95% CI, 0.76-2.14; p = 0.362) as well as between long-acting BZD use and risk of fractures (RR = 1.21; 95% CI, 0.95-1.54; p = 0.12). After accounting for publication bias, we observed that the overall association between BZD use and fracture risk to be slightly weaker (RR = 1.21; 95% CI, 1.13-1.30) but still significant. CONCLUSION The results of this meta-analysis demonstrate that the use of BZD, especially short-acting BZD, is associated with a moderate and clinically significant increase in fracture risk. However, large prospective studies that minimize selection bias are necessary to determine a more accurate fracture risk associated with BZD use.
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Affiliation(s)
- D Xing
- Department of Orthopaedics Institute, Tianjin Hospital, 406 Jiefang Nan Street, Hexi District, Tianjin, 300211, China
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Zhang Y, Yang JH. Activation of the PI3K/Akt pathway by oxidative stress mediates high glucose-induced increase of adipogenic differentiation in primary rat osteoblasts. J Cell Biochem 2013; 114:2595-602. [DOI: 10.1002/jcb.24607] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2013] [Accepted: 05/31/2013] [Indexed: 11/12/2022]
Affiliation(s)
- Yu Zhang
- College of Life Science; University of Chinese Academy of Sciences; 19A Yuquan Road; Beijing; 100049; People's Republic of China
| | - Jian-Hong Yang
- College of Life Science; University of Chinese Academy of Sciences; 19A Yuquan Road; Beijing; 100049; People's Republic of China
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Sheu Y, Marshall LM, Holton KF, Caserotti P, Boudreau RM, Strotmeyer ES, Cawthon PM, Cauley JA. Abdominal body composition measured by quantitative computed tomography and risk of non-spine fractures: the Osteoporotic Fractures in Men (MrOS) Study. Osteoporos Int 2013; 24:2231-41. [PMID: 23471565 PMCID: PMC3947542 DOI: 10.1007/s00198-013-2322-9] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2012] [Accepted: 01/30/2013] [Indexed: 12/25/2022]
Abstract
UNLABELLED The effect of abdominal adiposity and muscle on fracture is unclear in older men; therefore, we examined the association among 749 men aged 65+. Among various adipose tissues and muscle groups, lower psoas muscle volume and higher fatty infiltration of abdominal muscle contribute to higher fracture risk independent of BMD. INTRODUCTION The association of abdominal adiposity and muscle composition with incident fracture is unclear, especially in older men. Therefore, we examined the relationship of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), abdominal intermuscular adipose tissue (IMAT), and muscle volume with incident non-spine fractures among 749 men aged 65 and older. METHODS A case-cohort study design was used with a total of 252 fracture cases and 497 non-cases. We measured volumes (in centimeters) of adipose and muscle tissues obtained from quantitative computed tomography scan at the L4-5 intervertebral space. Three groups of muscle and IMAT were evaluated: total abdominal, psoas, and paraspinal. Cox proportional hazards regression with a robust variance estimator was used to estimate the hazard ratio (HR) of non-spine fractures per standard deviation (SD) increase in the abdominal body composition measures. The mean age among men in the random subcohort was 74.2 ± 6.1 years, and the average follow-up time was 5.2 ± 1.1 years. RESULTS After adjusting for age, race, clinic site, percent body fat, and femoral neck bone mineral density (BMD), no significant relationship was found between incident fractures and SAT or VAT. One SD increase in muscle volume at the psoas, but not paraspinal, was associated with 28 % lower fracture risk (95 % CI = 0.55-0.95). When IMAT models were further adjusted for corresponding muscle volumes, only abdominal IMAT was significantly associated with fracture risk (HR = 1.30 (95 % CI = 1.04-1.63)). CONCLUSION Our findings suggest that lower total psoas muscle volume and higher IMAT of the total abdominal muscle contribute to higher fracture risk in older men independent of BMD.
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Affiliation(s)
- Y Sheu
- Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA.
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Joshi A, Varthakavi P, Chadha M, Bhagwat N. A study of bone mineral density and its determinants in type 1 diabetes mellitus. J Osteoporos 2013; 2013:397814. [PMID: 23607045 PMCID: PMC3628496 DOI: 10.1155/2013/397814] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2012] [Revised: 01/18/2013] [Accepted: 02/21/2013] [Indexed: 01/22/2023] Open
Abstract
Type 1 diabetes mellitus (T1DM) has been inconsistently associated with low bone mineral density (BMD) and increased fracture risk. 86 consecutive T1DM cases and 140 unrelated age and sex matched healthy nondiabetic controls were included in the study. After history and examination, BMD and body composition were assessed by dual energy X-ray absorptiometry (DXA). Serum samples were analyzed for calcium, phosphorus, albumin, creatinine, alkaline phosphatase, 25 (OH) vitamin D3, intact parathormone (PTH) levels (both cases and controls) and HbA1c, antimicrosomal and IgA tissue transglutaminase (IgA TTG) antibodies, cortisol, follicle stimulating hormone (FSH), testosterone, sex hormone binding globulin (SHBG), tetraiodothyronine (T4), thyroid stimulating hormone (TSH), growth hormone (GH), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein 3 (IGFBP3) (cases only). T1DM cases had a lower BMD as compared to controls at both total body (TB) and lumbar spine (LS) (P < 0.05). Patients with celiac autoimmunity (CA) had significantly, lower BMD as compared to age, sex, and body mass index (BMI) matched T1DM controls. Linear regression analysis showed that low BMD in T1DM patients was associated with poor glycaemic control, lower IGF-1 levels, less physical activity (in total population as well as in male and female subgroups), and lower body fat percentage (in females) and higher alkaline phosphatase level (in males) (P < 0.05).
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Affiliation(s)
- Ameya Joshi
- Departmnent of Endocrinology, Topiwala National Medical College & BYL Nair Hospital, Mumbai 400008, India
| | - Premlata Varthakavi
- Departmnent of Endocrinology, Topiwala National Medical College & BYL Nair Hospital, Mumbai 400008, India
| | - Manoj Chadha
- Departmnent of Endocrinology, Topiwala National Medical College & BYL Nair Hospital, Mumbai 400008, India
| | - Nikhil Bhagwat
- Departmnent of Endocrinology, Topiwala National Medical College & BYL Nair Hospital, Mumbai 400008, India
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Ishida K, Haudenschild DR. Interactions between FGF21 and BMP-2 in osteogenesis. Biochem Biophys Res Commun 2013; 432:677-82. [PMID: 23416071 DOI: 10.1016/j.bbrc.2013.02.019] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2013] [Accepted: 02/06/2013] [Indexed: 12/13/2022]
Abstract
Lifestyle-related diseases are increasing and the challenge to create innovative drugs to treat such diseases is a main focus in medical science research. Fibroblast growth factor 21 (FGF21) is a powerful modulator of glucose and lipid metabolism, and is an innovative candidate drug already in clinical trials for type 2 diabetes mellitus and obesity. Bone fragility and impaired fracture healing induced by such lifestyle-related conditions are also a growing problem. Bone morphogenic proteins (BMPs) are well known osteogenic growth factors, and BMP-2 is used to augment bone formation in difficult clinical situations. There are many documented interactions between the FGF and BMP family proteins, although the interaction between FGF21 and BMP-2 remains unknown. The aim of this study was to reveal the effect of FGF21 toward BMP-2-dependent osteogenic activity, using C2C12 cells as a model system. We found that FGF21 enhanced BMP-2-dependent transcription and osteogenesis in the C2C12 cell line, which was confirmed by alkaline phosphatase activity, matrix mineralization, and gene expression. Mechanistically, FGF21 enhanced BMP-2-induced intracellular signaling through Smad proteins, but not through p44/42MAPK proteins. Furthermore, we identified a negative feedback loop in which BMP-2 decreased endogenous FGF21 mRNA expression. In summary, this study demonstrates interactions between BMP-2 and FGF21 pathways exist in vitro, and that FGF21 enhances the osteogenic activity of BMP-2 by up-regulating the BMP-2-dependent Smad signaling pathway.
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Affiliation(s)
- Kazunari Ishida
- Lawrence J.Ellison Musculoskeletal Research Center, Department of Orthopaedic Surgery, University of California Davis, 4635 Second Avenue, Sacramento, CA 95817, USA
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Rabenda V, Nicolet D, Beaudart C, Bruyère O, Reginster JY. Relationship between use of antidepressants and risk of fractures: a meta-analysis. Osteoporos Int 2013; 24:121-37. [PMID: 22638709 DOI: 10.1007/s00198-012-2015-9] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2011] [Accepted: 04/27/2012] [Indexed: 10/28/2022]
Abstract
UNLABELLED It has been shown that antidepressants would have a direct action on bone metabolism and would be associated with increased fracture risk. Results from this large meta-analysis show that both SSRIs and TCAs are associated with a moderate and clinically significant increase in the risk of fractures of all types. INTRODUCTION This study seeks to investigate the relationship between use of antidepressants and the risk of fracture. METHODS An exhaustive systematic research of case-control and cohort studies published or performed between 1966 and April 2011 that reported risk estimates of fracture associated with use of antidepressants was performed using MEDLINE, PsycINFO, and the Cochrane Systematic Review Database, manual review of the literature, and congressional abstracts. Inclusion, quality scoring, and data abstraction were performed systematically by three independent reviewers. RESULTS A total of 34 studies (n = 1,217,464 individuals) were identified. Compared with non-users, the random effects pooled RR of fractures of all types, among antidepressant users, were 1.39 (95%CI 1.32-1.47). Use of antidepressants were associated with a 42 %, 47 %, and 38 % risk increase in non-vertebral, hip, and spine fractures, respectively ([For non-vertebral fractures: RR = 1.42, 95%CI 1.34-1.51]; [For hip fractures: RR = 1.47, 95%CI 1.36-1.58]; [For spine fractures: RR = 1.38, 95%CI 1.19-1.61]). Studies examining SSRI use showed systematically a higher increase in the risk of fractures of all types, non-vertebral, and hip fractures than studies evaluating TCA use. CONCLUSIONS Results from this large meta-analysis show that both SSRIs and TCAs are associated with a moderate and clinically significant increase in the risk of fractures of all types.
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Affiliation(s)
- V Rabenda
- Department of Public Health, Epidemiology and Health Economics, University of Liège, CHU-Bât. B23, 4000, Liège, Belgium.
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39
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Wan Y. Bone marrow mesenchymal stem cells: fat on and blast off by FGF21. Int J Biochem Cell Biol 2012; 45:546-9. [PMID: 23270727 DOI: 10.1016/j.biocel.2012.12.014] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2012] [Revised: 12/04/2012] [Accepted: 12/16/2012] [Indexed: 12/31/2022]
Abstract
Bone marrow mesenchymal stem cells (BMMSCs) are multipotent marrow stromal cells with the ability to differentiate into a variety of cell types required for tissue regeneration including osteoblasts and chondrocytes. Thus, they hold tremendous potential as powerful therapeutic strategies for the prevention and treatment of degenerative disorders including osteoporosis and osteoarthritis. The differentiation of BMMSCs into competing lineages such as osteoblasts and marrow adipocytes is regulated by various environmental cues and intrinsic signaling pathways. Here I highlight recent advances in the understanding of BMMSC function and regulation, including the interaction between BMMSCs with the hematopoietic/immune system, and the identification of novel modulators of BMMSC differentiation such as the metabolic hormone fibroblast growth factor 21 (FGF21). These new findings will further elucidate the dynamic regulation of BMMSCs in the pathophysiological control of skeletal homeostasis, and facilitate the clinical applications of BMMSCs in regenerative medicine.
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Affiliation(s)
- Yihong Wan
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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40
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Wang G, He M, Yi P, Wang J, Li B, Li J, Fu Y, Bai L, Fu Q. Comparison of effects of vanadium absorbed by Coprinus comatus with those of inorganic vanadium on bone in streptozotocin-diabetic rats. Biol Trace Elem Res 2012; 149:391-8. [PMID: 22549703 DOI: 10.1007/s12011-012-9437-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2012] [Accepted: 04/19/2012] [Indexed: 11/27/2022]
Abstract
The purpose of this study was to compare the effect of vanadium absorbed by Coprinus comatus (VACC) with inorganic vanadium (vanadium nitrate, IV) in preventing diabetes-related osteopenia in streptozotocin-diabetic rats. Sixty Wistar female rats used were divided into four groups: (1) normal rats (control), (2) diabetic rats, (3) diabetic rats treated with VACC, and (4) diabetic rats treated with vanadium nitrate. A standardized type 1-like diabetes model was induced by injection of streptozotocin. After the rats were treated orally with VACC and IV respectively, plasma glucose, body weights, micro-CT, biomechanical testing, and histomorphometry were examined. In addition, bone samples were obtained to evaluate the content of mineral substances in bones. Treatments were performed over a 12-week period. Both VACC and IV have a positive effect on plasma glucose and body weights of STZ-induced diabetic rats. However, treatment with IV only caused a 39.6 % decrease in glucose levels and a 14.6 % increase in body weights, whereas VACC decreased plasma glucose and increased body weights by up to 52.2 and 24.5 %, respectively. At the same time, VACC significantly improved trabecular microstructure and mechanical strength, while IV did not exhibit desirable such effects. Also, bone Ca and bone P were not significantly increased by IV. These results indicated that both VACC and IV have hypoglycemic activity on diabetic rats, while IV did not improve bone properties. In conclusion, this study suggests that VACC improves diabetes-related bone dysfunction, primarily by improving the diabetic states.
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Affiliation(s)
- Guangbin Wang
- Department of Orthopaedics, ShengJing Hospital, China Medical University, Shenyang, People's Republic of China
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Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ. Proc Natl Acad Sci U S A 2012; 109:3143-8. [PMID: 22315431 DOI: 10.1073/pnas.1200797109] [Citation(s) in RCA: 332] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The endocrine hormone fibroblast growth factor 21 (FGF21) is a powerful modulator of glucose and lipid metabolism and a promising drug for type 2 diabetes. Here we identify FGF21 as a potent regulator of skeletal homeostasis. Both genetic and pharmacologic FGF21 gain of function lead to a striking decrease in bone mass. In contrast, FGF21 loss of function leads to a reciprocal high-bone-mass phenotype. Mechanistically, FGF21 inhibits osteoblastogenesis and stimulates adipogenesis from bone marrow mesenchymal stem cells by potentiating the activity of peroxisome proliferator-activated receptor γ (PPAR-γ). Consequently, FGF21 deletion prevents the deleterious bone loss side effect of the PPAR-γ agonist rosiglitazone. Therefore, FGF21 is a critical rheostat for bone turnover and a key integrator of bone and energy metabolism. These results reveal that skeletal fragility may be an undesirable consequence of chronic FGF21 administration.
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Hamann C, Kirschner S, Günther KP, Hofbauer LC. Bone, sweet bone--osteoporotic fractures in diabetes mellitus. Nat Rev Endocrinol 2012; 8:297-305. [PMID: 22249517 DOI: 10.1038/nrendo.2011.233] [Citation(s) in RCA: 282] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Diabetes mellitus adversely affects the skeleton and is associated with an increased risk of osteoporosis and fragility fractures. The mechanisms underlying low bone strength are not fully understood but could include impaired accrual of peak bone mass and diabetic complications, such as nephropathy. Type 1 diabetes mellitus (T1DM) affects the skeleton more severely than type 2 diabetes mellitus (T2DM), probably because of the lack of the bone anabolic actions of insulin and other pancreatic hormones. Bone mass can remain high in patients with T2DM, but it does not protect against fractures, as bone quality is impaired. The class of oral antidiabetic drugs known as glitazones can promote bone loss and osteoporotic fractures in postmenopausal women and, therefore, should be avoided if osteoporosis is diagnosed. A physically active, healthy lifestyle and prevention of diabetic complications, along with calcium and vitamin D repletion, represent the mainstay of therapy for osteoporosis in patients with T1DM or T2DM. Assessment of BMD and other risk factors as part of the diagnostic procedure can help design tailored treatment plans. All osteoporosis drugs seem to be effective in patients with diabetes mellitus. Increased awareness of osteoporosis is needed in view of the growing and aging population of patients with diabetes mellitus.
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Affiliation(s)
- Christine Hamann
- Department of Orthopedics, Dresden Technical University Medical Center, Fetscherstrasse 74, 01307 Dresden, Germany
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Bandeira E, Neves AP, Costa C, Bandeira F. Association between vascular calcification and osteoporosis in men with type 2 diabetes. J Clin Densitom 2012; 15:55-60. [PMID: 22071025 DOI: 10.1016/j.jocd.2011.07.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2011] [Revised: 06/03/2011] [Accepted: 07/07/2011] [Indexed: 10/15/2022]
Abstract
Atherosclerotic vascular disease is common in diabetes, and some data support a link with bone loss. This study evaluates the association between osteoporosis and clinical and metabolic factors and chronic complications of diabetes. We studied 59 diabetic men aged 50-80 yr who were assessed with bone densitometry (dual-energy X-ray absorptiometry). Of them, 10.2% of the patients were found to have osteoporosis in the lumbar spine and 45.8% osteopenia, whereas in the femoral neck, 11.8% had osteoporosis and 49% had osteopenia. There was a significant association of osteoporosis in the lumbar spine L1-L4 (p=0.004) and in the femoral neck (p=0.036) with iliac artery calcification. In addition, there was no association with any other metabolic factors, clinical factors, or chronic complications of diabetes evaluated, except for an association between a previous personal history of fractures (p=0.016) and low bone mineral density in the femoral neck. In conclusion, we found a positive association between the iliac artery calcification and osteoporosis in type 2 diabetic male patients.
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Affiliation(s)
- Elba Bandeira
- Agamenon Magalhães Hospital, Pernambuco University, Recife-PE Brazil.
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Thiazolidinediones on PPARγ: The Roles in Bone Remodeling. PPAR Res 2011; 2011:867180. [PMID: 22135675 PMCID: PMC3205770 DOI: 10.1155/2011/867180] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2011] [Revised: 10/04/2011] [Accepted: 10/05/2011] [Indexed: 01/02/2023] Open
Abstract
Thiazolidinediones (TZDs) are synthetic PPARγ (peroxisome proliferator-activated receptor gamma) agonists and a class of drugs for diabetes mellitus type 2 that can decrease blood sugar efficiently by enhancing insulin sensitivity. However, increased bone fracture risk in diabetic individuals treated with TZDs is one of the reported side effects. Recent studies show that TZDs such as rosiglitazone simultaneously inhibit osteoblast differentiation and activate osteoclast differentiation, leading to bone loss due to decreased bone formation and increased bone resorption. Furthermore, TZDs may activate PPARγ in tissues other than bone, such as the hypothalamus-pituitary-gonad (HPG) axis to indirectly regulate bone mass. This paper will focus on current new developments that implicate potential mechanisms for how PPARγ modulates skeletal homeostasis and how TZDs exert bone-loss side effects.
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45
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Pei Y, Fu Q. The effects of vanadium (V) absorbed by Coprinus comatus on bone in streptozotocin-induced diabetic rats. Biol Trace Elem Res 2011; 142:748-59. [PMID: 20734239 DOI: 10.1007/s12011-010-8825-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2010] [Accepted: 08/12/2010] [Indexed: 10/19/2022]
Abstract
The purpose of this study was to evaluate the effects of vanadium absorbed by Coprinus comatus (VACC) treatment on bone in streptozotocin (STZ)-induced diabetic rats. Forty-five Wistar female rats used were divided into three groups: (1) normal rats (control), (2) diabetic rats, and (3) diabetic rats treated with VACC. Normal and diabetic rats were given physiological saline, and VACC-treated rats were administered VACC intragastrically at doses of 0.18 mg vanadium/kg body weight once daily. Treatments were performed over a 12-week period. At sacrifice, one tibia and one femur were removed, subjected to micro computed tomography (micro-CT) for determination of trabecular bone structure, and then processed for histomorphometry to assess bone turnover. Another femoral was used for mechanical testing. In addition, bone samples were collected to evaluate the content of mineral substances in bones. Treatment with VACC increased trabecular bone volume fraction in diabetic rats. Vanadium-treated animals had significant increases in ultimate load, trabecular thickness, and osteoblast surface. However, vanadium treatment did not seem to affect bone stiffness, bone energy absorption, trabecular separation, and osteoclast number. P levels in the femurs of diabetic rats treated with VACC were significantly higher than those of diabetic animals. Ca levels in diabetic and diabetic rats treated with vanadium showed no obvious changes. In conclusion, our results provide an important proof of concept that VACC may represent a powerful approach to treating or reversing diabetic osteopathy in humans.
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Affiliation(s)
- Yi Pei
- Department of Orthopaedics, ShengJing Hospital, China Medical University, Shenyang, Liaoning, People's Republic of China
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46
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Moseley KF, Dobrosielski DA, Stewart KJ, Sellmeyer DE, Jan De Beur SM. Lean mass predicts hip geometry in men and women with non-insulin-requiring type 2 diabetes mellitus. J Clin Densitom 2011; 14:332-9. [PMID: 21652249 PMCID: PMC3150220 DOI: 10.1016/j.jocd.2011.04.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2011] [Revised: 04/12/2011] [Accepted: 04/14/2011] [Indexed: 12/25/2022]
Abstract
Persons with type 2 diabetes mellitus (T2DM) are at increased risk for hip fracture despite normal bone mineral density (BMD). The contribution of body composition to hip geometry, a measure of hip strength, has not been studied in T2DM. We hypothesized that lean mass would predict hip geometry. Subjects (n=134) for this cross-sectional analysis were men and women aged 56 ± 6yr with non-insulin-requiring T2DM. Fat and lean mass were measured with dual-energy X-ray absorptiometry (DXA). Abdominal fat was measured with magnetic resonance imaging. Hip geometry parameters including section modulus, cross-sectional area, and buckling ratio were estimated from DXA using validated formulae. Subjects had normal BMD, elevated body mass indices (29-41 kg/m(2)), and controlled T2DM (hemoglobin A1c: 5.1-8.3%). In bivariate analysis, lean mass was positively associated with section modulus and cross-sectional area in both sexes (r=0.36-0.55, p<0.05). In multivariate analyses, lean mass remained a significant predictor of all hip strength estimates in both sexes. In women alone, fat mass predicted parameters of hip strength. These data demonstrate that lean mass is significantly associated with hip strength in subjects with non-insulin-requiring T2DM. Resistance exercises that build lean mass may be an intervention for hip fracture prevention in T2DM, although additional research is needed.
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Affiliation(s)
- Kendall F. Moseley
- Division of Endocrinology & Metabolism, The Johns Hopkins Hospital, Baltimore, MD, USA
| | | | - Kerry J. Stewart
- Division of Cardiology, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA
| | - Deborah E. Sellmeyer
- Division of Endocrinology & Metabolism, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA
| | - Suzanne M. Jan De Beur
- Division of Endocrinology & Metabolism, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA
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Nyman JS, Even JL, Jo CH, Herbert EG, Murry MR, Cockrell GE, Wahl EC, Bunn RC, Lumpkin CK, Fowlkes JL, Thrailkill KM. Increasing duration of type 1 diabetes perturbs the strength-structure relationship and increases brittleness of bone. Bone 2011; 48:733-40. [PMID: 21185416 PMCID: PMC3062641 DOI: 10.1016/j.bone.2010.12.016] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2010] [Revised: 12/13/2010] [Accepted: 12/14/2010] [Indexed: 02/06/2023]
Abstract
Type 1 diabetes (T1DM) increases the likelihood of a fracture. Despite serious complications in the healing of fractures among those with diabetes, the underlying causes are not delineated for the effect of diabetes on the fracture resistance of bone. Therefore, in a mouse model of T1DM, we have investigated the possibility that a prolonged state of diabetes perturbs the relationship between bone strength and structure (i.e., affects tissue properties). At 10, 15, and 18 weeks following injection of streptozotocin to induce diabetes, diabetic male mice and age-matched controls were examined for measures of skeletal integrity. We assessed 1) the moment of inertia (I(MIN)) of the cortical bone within diaphysis, trabecular bone architecture of the metaphysis, and mineralization density of the tissue (TMD) for each compartment of the femur by micro-computed tomography and 2) biomechanical properties by three-point bending test (femur) and nanoindentation (tibia). In the metaphysis, a significant decrease in trabecular bone volume fraction and trabecular TMD was apparent after 10 weeks of diabetes. For cortical bone, type 1 diabetes was associated with decreased cortical TMD, I(MIN), rigidity, and peak moment as well as a lack of normal age-related increases in the biomechanical properties. However, there were only modest differences in material properties between diabetic and normal mice at both whole bone and tissue-levels. As the duration of diabetes increased, bone toughness decreased relative to control. If the sole effect of diabetes on bone strength was due to a reduction in bone size, then I(MIN) would be the only significant variable explaining the variance in the maximum moment. However, general linear modeling found that the relationship between peak moment and I(MIN) depended on whether the bone was from a diabetic mouse and the duration of diabetes. Thus, these findings suggest that the elevated fracture risk among diabetics is impacted by complex changes in tissue properties that ultimately reduce the fracture resistance of bone.
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Affiliation(s)
- Jeffry S Nyman
- Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 27212, USA.
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Jang WG, Kim EJ, Bae IH, Lee KN, Kim YD, Kim DK, Kim SH, Lee CH, Franceschi RT, Choi HS, Koh JT. Metformin induces osteoblast differentiation via orphan nuclear receptor SHP-mediated transactivation of Runx2. Bone 2011; 48:885-93. [PMID: 21147283 DOI: 10.1016/j.bone.2010.12.003] [Citation(s) in RCA: 141] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2010] [Revised: 11/30/2010] [Accepted: 12/06/2010] [Indexed: 12/24/2022]
Abstract
Metformin is an oral anti-diabetic drug of the biguanide class that is commonly used to treat type 2 diabetes mellitus. This study examined the molecular mechanism for the action of metformin on osteoblast differentiation. Metformin-induced mRNA expression of the osteogenic genes and small heterodimer partner (SHP) in MC3T3E1 cells were determined by RT-PCR and real-time PCR. Metformin increased significantly the expression of the key osteogenic genes, such as alkaline phosphatase (ALP), osteocalcin (OC) and bone sialoprotein (BSP) as well as SHP. Transient transfection assays were performed in MC3T3E1 cells to confirm the effects of metformin on SHP, OC and Runx2 promoter activities. Metformin increased the transcription of the SHP and OC genes, and the metformin effect was inhibited by dominant negative form of AMPK (DN-AMPK) or compound C (an inhibitor of AMPK). The adenoviral overexpression of SHP increased significantly the level of ALP staining and OC production. However, metformin did not have any significant effect on osteogenic gene expression, ALP staining and activity, and OC production in SHP null (SHP-/-) primary calvarial cells. Moreover, upstream stimulatory factor-1 (USF-1) specifically mediated metformin-induced SHP gene expression. In addition, metformin-induced AMPK activation increased the level of Runx2 mRNA and protein. However, USF-1 and SHP were not involved in metformin-induced Runx2 expression. Transient transfection and chromatin immunoprecipitation assays confirmed that metformin-induced SHP interacts physically and forms a complex with Runx2 on the osteocalcin gene promoter in MC3T3E1 cells. These results suggest that metformin may stimulate osteoblast differentiation through the transactivation of Runx2 via AMPK/USF-1/SHP regulatory cascade in mouse calvaria-derived cells.
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Affiliation(s)
- Won Gu Jang
- Dental Science Research Institute and BK21, School of Dentistry, Chonnam National University, Gwangju 500-757, Republic of Korea.
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McIntosh B, Cameron C, Singh SR, Yu C, Ahuja T, Welton NJ, Dahl M. Second-line therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a systematic review and mixed-treatment comparison meta-analysis. OPEN MEDICINE : A PEER-REVIEWED, INDEPENDENT, OPEN-ACCESS JOURNAL 2011; 5:e35-48. [PMID: 22046219 PMCID: PMC3205809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/17/2010] [Revised: 10/15/2010] [Accepted: 11/01/2010] [Indexed: 11/24/2022]
Abstract
BACKGROUND Although there is general agreement that metformin should be used as first-line pharmacotherapy in patients with type 2 diabetes, uncertainty remains regarding the choice of second-line therapy once metformin is no longer effective. We conducted a systematic review and meta-analysis to assess the comparative safety and efficacy of all available classes of antihyperglycemic therapies in patients with type 2 diabetes inadequately controlled on metformin monotherapy. METHODS MEDLINE, EMBASE, BIOSIS Previews, PubMed and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials published in English from 1980 to October 2009. Additional citations were obtained from grey literature and conference proceedings and through stakeholder feedback. Two reviewers independently selected studies, extracted data and assessed risk of bias. Key outcomes of interest were hemoglobin A1c, body weight, hypoglycemia, quality of life, long-term diabetes-related complications, serious adverse drug events and mortality. Mixed-treatment comparison and pairwise meta-analyses were conducted to pool trial results, when appropriate. RESULTS We identified 49 active and non-active controlled randomized trials that compared 2 or more of the following classes of antihyperglycemic agents and weight-loss agents: sulfonylureas, meglitinides, thiazolidinediones (TZDs), dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) analogues, insulins, alpha-glucosidase inhibitors, sibutramine and orlistat. All classes of second-line antihyperglycemic therapies achieved clinically meaningful reductions in hemoglobin A1c (0.6% to 1.0%). No significant differences were found between classes. Insulins and insulin secretagogues were associated with significantly more events of overall hypoglycemia than the other agents, but severe hypoglycemia was rarely observed. An increase in body weight was observed with the majority of second-line therapies (1.8 to 3.0 kg), the exceptions being DPP-4 inhibitors, alpha-glucosidase inhibitors and GLP-1 analogues (0.6 to -1.8 kg). There were insufficient data available for diabetes complications, mortality or quality of life. INTERPRETATION DPP-4 inhibitors and GLP-1 analogues achieved improvements in glycemic control similar to those of other second-line therapies, although they may have modest benefits in terms of weight gain and overall hypoglycemia. Further long-term trials of adequate power are required to determine whether newer drug classes differ from older agents in terms of clinically meaningful outcomes.
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Pentosidina: un nuevo biomarcador de las complicaciones en la diabetes mellitus. Med Clin (Barc) 2011; 136:298-302. [DOI: 10.1016/j.medcli.2009.12.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2009] [Revised: 11/26/2009] [Accepted: 12/01/2009] [Indexed: 12/31/2022]
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