Pathophysiological mechanism of bone loss in type 2 diabetes involves inverse regulation of osteoblast function by pgc-1a and skeletal muscle atrogenes: Adipor1 as a potential target for reversing diabetes-induced osteopenia

Mohd Parvez Khan, Abhishek Kumar Singh, Amit Arvind Joharapurkar, Manisha Yadav, Sonal Shree, Harish Kumar, Anagha Gurjar, Jay Sharan Mishra, Mahesh Chandra Tiwari, Geet Kumar Nagar, Sudhir Kumar, Ravishankar Ramachandran, Anupam Sharan, Mukul Rameshchandra Jain, Arun Kumar Trivedi, Rakesh Maurya, Madan Madhav Godbole, Jiaur Rahaman Gayen, Sabyasachi Sanyal, Naibedya Chattopadhyay

Research output: Contribution to journalArticle

28 Scopus citations

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 g coactivator 1 - A (PGC-1a) 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. Osteoblastspecific PGC-1a upregulation by 6-C-b-d-glucopyranosyl- (2S,3S)-(+)-5,7,39,49-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-1a 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-1a upregulation in osteoblasts could reverse type 2 diabetes-associated deterioration in skeletal health.

Original languageEnglish (US)
Pages (from-to)2609-2623
Number of pages15
JournalDiabetes
Volume64
Issue number7
DOIs
StatePublished - Jul 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

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    Khan, M. P., Kumar Singh, A., Joharapurkar, A. A., Yadav, M., Shree, S., Kumar, H., Gurjar, A., Mishra, J. S., Tiwari, M. C., Kumar Nagar, G., Kumar, S., Ramachandran, R., Sharan, A., Jain, M. R., Kumar Trivedi, A., Maurya, R., Godbole, M. M., Gayen, J. R., Sanyal, S., & Chattopadhyay, N. (2015). Pathophysiological mechanism of bone loss in type 2 diabetes involves inverse regulation of osteoblast function by pgc-1a and skeletal muscle atrogenes: Adipor1 as a potential target for reversing diabetes-induced osteopenia. Diabetes, 64(7), 2609-2623. https://doi.org/10.2337/db14-1611