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Diabetes. 2015 Jul;64(7):2609-23. doi: 10.2337/db14-1611. Epub 2015 Jan 29.

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.

Author information

1
Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
2
Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
3
Zydus Research Centre, Ahmedabad, Gujarat, India.
4
Division of Molecular and Structural Biology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
5
Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
6
Vinayak Cosmetic Surgery & Laser Centre, Lucknow, Uttar Pradesh, India.
7
Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.
8
Division of Pharmacokinetics and Metabolism, CSIR-Central Drug Research Institute, Lucknow, UP, India.
9
Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India sanyal@cdri.res.in n_chattopadhyay@cdri.res.in.
10
Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India sanyal@cdri.res.in n_chattopadhyay@cdri.res.in.

Abstract

Type 2 diabetes is associated with increased fracture risk and delayed fracture healing; the underlying mechanism, however, remains poorly understood. We systematically investigated skeletal pathology in leptin receptor-deficient diabetic mice on a C57BLKS background (db). Compared with wild type (wt), db mice displayed reduced peak bone mass and age-related trabecular and cortical bone loss. Poor skeletal outcome in db mice contributed high-glucose- and nonesterified fatty acid-induced osteoblast apoptosis that was associated with peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) downregulation and upregulation of skeletal muscle atrogenes in osteoblasts. Osteoblast depletion of the atrogene muscle ring finger protein-1 (MuRF1) protected against gluco- and lipotoxicity-induced apoptosis. Osteoblast-specific PGC-1α upregulation by 6-C-β-d-glucopyranosyl-(2S,3S)-(+)-5,7,3',4'-tetrahydroxydihydroflavonol (GTDF), an adiponectin receptor 1 (AdipoR1) agonist, as well as metformin in db mice that lacked AdipoR1 expression in muscle but not bone restored osteopenia to wt levels without improving diabetes. Both GTDF and metformin protected against gluco- and lipotoxicity-induced osteoblast apoptosis, and depletion of PGC-1α abolished this protection. Although AdipoR1 but not AdipoR2 depletion abolished protection by GTDF, metformin action was not blocked by AdipoR depletion. We conclude that PGC-1α upregulation in osteoblasts could reverse type 2 diabetes-associated deterioration in skeletal health.

PMID:
25633418
DOI:
10.2337/db14-1611
[Indexed for MEDLINE]
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