Pathophysiological Mechanism of Bone Loss in Type 2 Diabetes Involves Inverse Regulation of Osteoblast Function by PGC-1α and Skeletal Muscle Atrogenes: AdipoR1 as a Potential Target for Reversing Diabetes-Induced Osteopenia
| Autor: | Jay S. Mishra, Mohd Parvez Khan, Geet Kumar Nagar, Sudhir Kumar, Manisha Yadav, Ravishankar Ramachandran, Sonal Shree, Anupam Sharan, Sabyasachi Sanyal, Arun Kumar Trivedi, Mukul R. Jain, Rakesh Maurya, Abhishek Singh, Jiaur R. Gayen, Mahesh Chandra Tiwari, Harish Kumar, Naibedya Chattopadhyay, Anagha Gurjar, Amit Joharapurkar, Madan M. Godbole |
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| Rok vydání: | 2015 |
| Předmět: |
medicine.medical_specialty
Endocrinology Diabetes and Metabolism Muscle Proteins Mice Insulin resistance Downregulation and upregulation Bone Density Internal medicine Internal Medicine medicine Animals Muscle Skeletal Adiponectin receptor 1 Osteoblasts Errata Chemistry Leptin Skeletal muscle Osteoblast medicine.disease Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Metformin Mice Inbred C57BL Osteopenia Bone Diseases Metabolic Endocrinology medicine.anatomical_structure Diabetes Mellitus Type 2 Insulin Resistance Receptors Adiponectin Transcription Factors medicine.drug |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db14-1611 |
| Popis: | Type 2 diabetes is associated with increased fracture risk and delayed facture healing; the underlying mechanism, however, remains poorly understood. We systematically investigated skeletal pathology in leptin receptor–deficient diabetic mice on a C57BLKS background (db). Compared with wild type (wt), db mice displayed reduced peak bone mass and age-related trabecular and cortical bone loss. Poor skeletal outcome in db mice contributed high-glucose– and nonesterified fatty acid–induced osteoblast apoptosis that was associated with peroxisome proliferator–activated receptor γ coactivator 1-α (PGC-1α) downregulation and upregulation of skeletal muscle atrogenes in osteoblasts. Osteoblast depletion of the atrogene muscle ring finger protein-1 (MuRF1) protected against gluco- and lipotoxicity-induced apoptosis. Osteoblast-specific PGC-1α upregulation by 6-C-β-d-glucopyranosyl-(2S,3S)-(+)-5,7,3′,4′-tetrahydroxydihydroflavonol (GTDF), an adiponectin receptor 1 (AdipoR1) agonist, as well as metformin in db mice that lacked AdipoR1 expression in muscle but not bone restored osteopenia to wt levels without improving diabetes. Both GTDF and metformin protected against gluco- and lipotoxicity-induced osteoblast apoptosis, and depletion of PGC-1α abolished this protection. Although AdipoR1 but not AdipoR2 depletion abolished protection by GTDF, metformin action was not blocked by AdipoR depletion. We conclude that PGC-1α upregulation in osteoblasts could reverse type 2 diabetes–associated deterioration in skeletal health. |
| Databáze: | OpenAIRE |
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