Conjugated Linoleic Acid (CLA) co-treatment alleviates antidiabetic drug, rosiglitazone associated deterioration of bone remodeling

Abstract

Diabetes mellitus (DM) is a chronic metabolic disease characterized by hyperglycemia due to decreased insulin secretion, defective action or both. The rosiglitazone (RSG) is one of the oral antidiabetic drug used in type 2 (T2) DM and has a unique insulin-sensitizing capacity. However, RSG has a negative side effect on the bone as it stimulates the differentiation of bone marrow-mesenchymal stromal cells (BM-MSCs) into adipocytes at the expense of osteoblasts in the bone marrow microenvironment, disturbing the normal balance of bone remodeling and causing BM adiposity. On the other hand, the trans-10,cis-12 conjugated linoleic acid (CLA), a fatty acid is known as anti-adipogenic, pro-osteogenic. Therefor, this study was designed to assess whether CLA can alleviate the negative effect of RSG on bone. We used adipose tissue derived-mesenchymal stem cells (AT-MSCs) as a human in vitro model to study the effect of CLA, RSG and combined treatment (RSG+CLA) on the osteoblastogenic and adipogenic differentiation of AT-MSCs. Osteoblastogenesis was assessed by Alizarin Red Staining and bone mineralization was assessed by ?"OsteoImage" ?^TMassays, whereas adipogenesis was assessed by Oil Red O Staining and LipidTOX assays. Besides, the level of expression of osteogenic and adipogenic markers was measured on treated osteo- and adipo-differentiated MSCs using real time RT-PCR, immunohistochemistry (IHC) and western blot analysis. Compared to RSG group, the combined treatment group stimulates osteoblastogenesis, as evidenced by increased mineralization and upregulation of osteogenic markers OPN and RUNX2 and inhibits adipogenesis in osteogenic media as showed by decreased lipid content and downregulation of adipogenic markers FABP4, LPL and adipsin. In conclusion, the use of CLA as an adjunctive treatment reversed the effects of RSG on osteogenesis and adipogenesis. Further preclinical and clinical studies will be undertaken to establish this treatment regimen for the successful treatment of diabetic patients with rosiglitazone without adverse side effects on bone.