Caveolin-1 Regulates Osteoclastogenesis and Bone Metabolism in a Sex-dependent Manner

Lipid raft microdomains have important roles in various cellular responses. Caveolae are a specialized type of lipid rafts that are stabilized by oligomers of caveolin proteins. Here, we show that caveolin-1 (Cav-1) plays a crucial role in the regulation of osteoclastogenesis. We found that caveolin-1 was dramatically up-regulated by receptor activator of nuclear.factor kappa B ligand (RANKI,), the osteoclast differentiation factor. Knockdown of Cav- I reduced osteodastogenesis and induction of NFATcl, the master transcription factor for osteoclastogenesis, by RANKL. Consistent with the in vitro results, injection of caveolin-1 siRNA onto mice calvariae showed reduction in RANK!,induced bone resorption and osteoclast formation. Moreover, Cav-1(-/-) female mice had higher bone volume and lower osteodast number compared with wild type mice. However, Cav-1(-/-) male mice had both osteoclast and osteoblast numbers higher than wild type mice with no difference in bone volume. The sex dependence in the effect of Cav- I deficiency was partly attributed to decreased receptor activator of nuclear factor kappa B and increased cFms expression in osteoclast precursors of female and male mice, respectively. Taken together, these data demonstrate that Cav-1 has a complicated but critical role for osteodastogenesis.