An insulin-sensitizing thiazolidinedione, which minimally activates PPARγ, does not cause bone loss


Tomohiro Fukunaga, Wei Zou, Nidhi Rohatgi, Jerry R. Colca and Steven L. Teitelbaum


Rosiglitazone is an insulin-sensitizing thiazolidinedione (TZD) which activates the transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ). While 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 PPARγ preferentially promotes formation of adipocytes at the cost of osteoblasts. Rosiglitazone-activated PPARγ, however, also stimulates osteoclast formation. A new TZD analog with low affinity for binding and activation of PPARγ 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 PPARγ target gene, CD36. MSDC-0602, in contrast, minimally activates PPARγ and does not alter CD36 expression in the bone resorptive cells. Consistent with this finding, rosiglitazone increases RANKL-induced osteoclast differentiation and number whereas MSDC-0602 fails to do. To determine if this new TZD analog is bone sparing, in vivo, we fed adult male C57BL/6 mice MSDC-0602 or rosiglitazone. 6-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 PPARγ-sparing eliminates the skeletal side effects of TZDs while maintaining their insulin-sensitizing properties.

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