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- Title
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.
- Authors
Khan, Mohd. Parvez; Singh, Abhishek Kumar; Joharapurkar, Amit Arvind; Yadav, Manisha; Shree, Sonal; Kumar, Harish; Gurjar, Anagha; Mishra, Jay Sharan; Tiwari, Mahesh Chandra; Nagar, Geet Kumar; Kumar, Sudhir; Ramachandran, Ravishankar; Sharan, Anupam; Jain, Mukul Rameshchandra; Trivedi, Arun Kumar; Maurya, Rakesh; Godbole, Madan Madhav; Gayen, Jiaur Rahaman; Sanyal, Sabyasachi; Chattopadhyay, Naibedya
- Abstract
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.
- Subjects
BONE physiology; BONE diseases; TYPE 2 diabetes; OSTEOPENIA; SKELETAL muscle physiology
- Publication
Diabetes, 2015, Vol 64, Issue 7, p2609
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db14-1611