Osteoblast-Targeted Overexpression of PPARγ Inhibited Bone Mass Gain in Male Mice and Accelerated Ovariectomy-Induced Bone Loss in Female Mice

PPAR gamma has critical role in the differentiation of mesenchymal stem cells into adipocytes while suppressing osteoblastic differentiation. We generated transgenic mice that overexpress PPAR gamma specifically in osteoblasts under the control of a 2.3-kb procollagen type 1 promoter (Col.1-PPAR gamma). Bone mineral density (BMD) of 6- to 14-week-old Col.1-PPAR gamma male mice was 8% to 10% lower than that of their wildtype littermates, whereas no difference was noticed in Col.1-PPAR gamma female mice. Col.1-PPAR gamma male mice exhibited decreased bone volume (45%), trabecular thickness (23%), and trabecular number (27%), with a reciprocal increase in trabecular spacing (51%). Dynamic histomorphometric analysis also revealed that bone-formation rate (42%) and mineral apposition rate (32%) were suppressed significantly in Col.1-PPAR gamma male mice compared with their wild-type littermates. Interestingly, osteoclast number and surface also were decreased by 40% and 58%, respectively, in Col.1-PPAR gamma male mice. In vitro whole-marrow culture for osteoclastogenesis also showed a significant decrease in osteoclast formation (approximately 35%) with the cells from Col.1-PPAR gamma male mice, and OPG/RANKL ratio was reduced in stromal cells from Col.1-PPAR gamma male mice. Although there was no significant difference in BMD in Col.1-PPARg female mice up to 30 weeks, bone loss was accelerated after ovariectomy compared with wild-type female mice (-3.9% versus -6.8% at 12 weeks after ovariectomy, p<.01), indicating that the effects of PPAR gamma overexpression becomes more evident in an estrogen-deprived state in female mice. In conclusion, in vivo osteoblast-specific overexpression of PPAR gamma negatively regulates bone mass in male mice and accelerates estrogen-deficiency-related bone loss in female mice. (C) 2011 American Society for Bone and Mineral Research.