17beta-estradiol downregulates beta3-integrin expression in differentiating and mature human osteoclasts

The increased bone resorption observed after estrogen withdrawal is responsible for bone loss and may lead to osteoporosis. The mechanism by which estradiol inhibits bone resorption is known to involve decreased osteoclastogenesis, however, the effect on osteoclast adhesion remains unclear. We examined the in vitro effect of estradiol and raloxifene on human osteoclast differentiation and function. Human peripheral blood mononuclear cells were cultured with M-CSF/RANK-L for 18 days, and we evaluated bone resorption, the expression of the protein and mRNA of the integrins, c-jun and c-fos in the presence or absence of estradiol. In this human model, beta3-integrin expression increased at the mRNA and protein levels during osteoclast differentiation, whereas that of beta5-integrin did not. We found that estradiol and raloxifene directly inhibited bone resorption on bone slices by 50%, and decreased the expression of beta3-integrin mRNA (60%) and protein (20%) in a time-dependent manner. Moreover, the mRNAs of c-fos and c-jun were both diminished by estradiol and raloxifene, particularly in early osteoclasts, but also to a lesser extent in mature cells. These findings suggest that the direct inhibitory action of estradiol on bone resorption may affect human osteoclast differentiation through downregulation of c-fos and c-jun and adhesion through modulation of beta3-integrin.