engleski

The role of Fas/Fas ligand system in estrogen deficiency-induced osteoporosis

Fas is a death receptor whose major function is mediation of T cell cytotoxicity and regulation of immune response. It is also ubiquitously expressed on various cell types where it is involved in regulation of differentiation and survival. Fas ligation induces apoptosis, but there is increasing evidence of non-apoptotic functions of Fas mediated by distinct signaling mechanisms dependent on the tissue type and other regulatory factors including cytokines, chemokines and growth factors. Fas is expressed on osteoblastic and osteoclastic cells, where it may, under specific circumstances, induce apoptosis. Fas may also inhibit osteoblast differentiation via caspase 8 dependent mechanism. It is hypothesized that estrogen deficiency upregulates Fas on osteoblasts, which may lead to increased osteoblast apoptosis and/or their decreased differentiation and contribute to bone loss. The aim of this study was to estimate importance of the proposed pathogenic mechanism in vivo. We first analyzed the expression of Fas gene four weeks after the ovariectomy in bones and bone cell cultures from wild-type mice, and confirmed increased Fas expression in total bone tissue and osteoblasts from ovariectomized compared to sham operated animals. Four weeks after ovariectomy in mice deficient for Fas gene (Fas -/-) we analyzed bone histomorphometric parameters and osteoblast and osteoclast differentiation in vitro. Bone volume was generally higher in Fas -/- mice than in wild-type controls, and significantly decreased after ovariectomy in wild-type mice, whereas it was unaltered in Fas -/- mice. Number of osteoclasts in vivo and osteoclastogenesis in vitro were increased after ovariectomy in wild-type mice, but unchanged in Fas -/- mice. Osteoblastogenesis in vitro was stimulated by ovariectomy in both mouse strains, and this effect was more pronounced in Fas -/- mice. Fas -/- osteoblasts expressed higher levels of osteoblast specific genes than the control osteoblasts. Osteoblast differentiation genes had similar expression patterns in sham operated and ovariectomized mice. Our findings show that Fas/Fas ligand system may have an important role in the pathogenesis of postmenopausal osteoporosis. Modulation of its effects on bone cells may contribute to the development of new strategies for osteoporosis treatment.

osteoporosis; osteoblasts; apoptosis; differentiation

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