An Insulin-Sensitizing Thiazolidinedione, Which Minimally Activates PPAR gamma, Does Not Cause Bone Loss

作者：Fukunaga Tomohiro; Zou Wei; Rohatgi Nidhi; Colca Jerry R; Teitelbaum Steven L^*

来源：Journal of Bone and Mineral Research, 2015, 30(3): 508-515.

DOI：10.1002/jbmr.2364

• TYPE II DIABETES MELLITUS
• THIAZOLIDINEDIONE
• OSTEOCLASTS
• BONE HISTOMORPHOMETRY
• BONE mu CT

Rosiglitazone is an insulin-sensitizing thiazolidinedione (TZD) that activates the transcription factor peroxisome proliferator-activated receptor gamma (PPAR gamma). Although rosiglitazone effectively treats type II diabetes mellitus (T2DM), it carries substantial complications, including increased fracture risk. This predisposition to fracture is consistent with the fact that PPAR gamma preferentially promotes formation of adipocytes at the cost of osteoblasts. Rosiglitazone-activated PPAR gamma, however, also stimulates osteoclast formation. A new TZD analog with low affinity for binding and activation of PPAR gamma but whose insulin-sensitizing properties mirror those of rosiglitazone has been recently developed. Because of its therapeutic implications, we investigated the effects of this new TZD analog (MSDC-0602) on skeletal homeostasis, in vitro and in vivo. Confirming it activates the nuclear receptor in osteoclasts, rosiglitazone enhances expression of the PPAR gamma target gene, CD36. MSDC-0602, in contrast, minimally activates PPAR gamma and does not alter CD36 expression in the bone-resorptive cells. Consistent with this finding, rosiglitazone increases receptor activator of NF-kappa B ligand (RANKL)-induced osteoclast differentiation and number, whereas MSDC-0602 fails to do so. To determine if this new TZD analog is bone sparing, in vivo, we fed adult male C57BL/6 mice MSDC-0602 or rosiglitazone. Six months of a rosiglitazone diet results in a 35% decrease in bone mass with increased number of osteoclasts, whereas that of MSDC-0602-fed mice is indistinguishable from control. Thus, PPAR gamma sparing eliminates the skeletal side effects of TZDs while maintaining their insulin-sensitizing properties.

• 出版日期2015-3