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.
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.
authors: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors: Mohd Parvez
authors: MP
authors: Khan
authors: Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors: Abhishek Kumar
authors: AK
authors: Singh
authors: Zydus Research Centre, Ahmedabad, Gujarat, India.
authors: Amit Arvind
authors: AA
authors: Joharapurkar
authors: Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors: Manisha
authors: M
authors: Yadav
authors: Division of Molecular and Structural Biology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors: Sonal
authors: S
authors: Shree
authors: Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors: Harish
authors: H
authors: Kumar
authors: Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors: Anagha
authors: A
authors: Gurjar
authors: Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors: Jay Sharan
authors: JS
authors: Mishra
authors: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors: Mahesh Chandra
authors: MC
authors: Tiwari
authors: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors: Geet Kumar
authors: GK
authors: Nagar
authors: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors: Sudhir
authors: S
authors: Kumar
authors: Division of Molecular and Structural Biology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors: Ravishankar
authors: R
authors: Ramachandran
authors: Vinayak Cosmetic Surgery & Laser Centre, Lucknow, Uttar Pradesh, India.
authors: Anupam
authors: A
authors: Sharan
authors: Zydus Research Centre, Ahmedabad, Gujarat, India.
authors: Mukul Rameshchandra
authors: MR
authors: Jain
authors: Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors: Arun Kumar
authors: AK
authors: Trivedi
authors: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors: Rakesh
authors: R
authors: Maurya
authors: Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.
authors: Madan Madhav
authors: MM
authors: Godbole
authors: Division of Pharmacokinetics and Metabolism, CSIR-Central Drug Research Institute, Lucknow, UP, India.
authors: Jiaur Rahaman
authors: JR
authors: Gayen
authors: Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India sanyal@cdri.res.in n_chattopadhyay@cdri.res.in.
authors: Sabyasachi
authors: S
authors: Sanyal
authors: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India sanyal@cdri.res.in n_chattopadhyay@cdri.res.in.
authors: Naibedya
authors: N
authors: Chattopadhyay
mesh_terms: D000818:Animals; D015519:Bone Density; D001851:Bone Diseases, Metabolic / Q000209:etiology* / Q000517:prevention & control; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D007333:Insulin Resistance; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism*; D010006:Osteoblasts / Q000502:physiology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D054419:Receptors, Adiponectin / Q000819:agonists / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D009124:Muscle Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D054419:Receptors, Adiponectin; D014157:Transcription Factors; C475419:adiponectin receptor 1, mouse