Modulation of survival in osteoblasts from postmenopausal women.

Osteoblast survival is one of the determinants of postmenopausal osteoporosis development. Recent data from animal experiments suggest that cytokines, in particular Fas ligand (FasL), contribute to postmenopausal osteoporosis. We now address the effect of Fas activation in postmenopausal osteoblast survival and the potential modulatory effect of estrogen and raloxifene analog (LY117018). The expression of Fas mRNA, Fas protein, and the sensitivity to Fas-induced apoptosis were studied in primary cultures of human osteoblasts from postmenopausal women and in osteoblastic MG-63 cells. Human postmenopausal osteoblasts constitutively expressed Fas receptors in the cell surface. TNFalpha increased the expression of Fas mRNA and cell surface Fas expression. Neither estradiol nor raloxifene analog prevented this increase in Fas expression. In addition, activation of Fas receptor resulted in apoptosis of postmenopausal osteoblasts. While TNFalpha did not induce human osteoblast apoptosis, it did increase the lethal effect of Fas activation. Therapeutic concentrations of estradiol or raloxifene analog did not modulate lethal cytokine-induced apoptosis. Both postmenopausal osteoblasts and MG-63 cells express FasL. FasL expression was not modulated by TNFalpha. In conclusion, estrogen and raloxifene analog do not appear to affect the sensitivity of postmenopausal osteoblasts to Fas-mediated apoptosis.