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

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

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)


Rosiglitazone is an insulin-sensitizing thiazolidinedione (TZD) that activates the transcription factor peroxisome proliferator-activated receptor gamma (PPARγ). 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 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 receptor activator of NF-kB 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, PPARγ sparing eliminates the skeletal side effects of TZDs while maintaining their insulin-sensitizing properties.

Original languageEnglish
Pages (from-to)508-515
Number of pages8
JournalJournal of Bone and Mineral Research
Issue number3
Publication statusPublished - 2015 Mar 1
Externally publishedYes


  • Bone histomorphometry
  • Bone μCT
  • Osteoclasts
  • Thiazolidinedione
  • Type II diabetes mellitus

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine


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