THE ESTROGEN-RECEPTORS INVOLVEMENT IN OSTEOBLASTS ADAPTIVE RESPONSE TO MECHANICAL STRAIN

The estrogen receptor's role in bone cells' response to mechanical str ain was investigated by studying the effect of the estrogen receptor m odulators ICI 182, 780 and tamoxifen on the proliferation of primary c ultures of rat long bone-derived osteoblasts stimulated by the indepen dent and combined effects of 17 beta-estradiol, mechanical strain, and the mitogens basic fibroblast growth factor (bFGF), truncated insulin -like growth factor (tIGF)-I and tIGF-II, and epidermal growth factor (EGF). 17 beta-estradiol (10(-10) M to 10(-8) M) increased [H-3]thymid ine incorporation equally in cells from males and females, as did a si ngle period of cyclical strain in the plastic strips onto which the ce lls had been seeded (peak strain 3,400 mu epsilon, 600 cycles, 1 Hz). At 10(-8) M, neither ICI 182,780 nor tamoxifen had any effect on basal [3H]thymidine incorporation in these cells, but both compounds preven ted their proliferative responses to 10(-8) M 17 beta-estradiol. Tamox ifen eliminated and ICI 182,780 substantially reduced the proliferatio n stimulated by strain. 17 beta-estradiol partially rescued the strain -related response from the effect of tamoxifen but not that of ICI 182 ,780. Both tamoxifen and ICI 182,780 reduced proliferation stimulated by 10(-8) M EGF but had no effect on that by 10(-7) M bFGF or tIGF-I a nd tIGF-II. That both ICI 182,780 and tamoxifen, which in other tissue s act as estrogen antagonists, should reduce osteoblast proliferation stimulated by 17 beta-estradiol and EGF, but not that by FGF or the IG Fs, was expected since the mitogenic effects of estrogen and EGF invol ve the estrogen receptor, whereas those of FGF and the IGFs do not. Th at these compounds should prevent osteoblasts' proliferative response to strain suggests that strain also stimulates mitogenesis by a mechan ism involving the estrogen receptor. If this is so, bones' reduced abi lity to maintain their structural strength after the menopause could b e explained by less effective strain-related (re)modeling when estroge n is absent and, among other changes, the estrogen receptor could be d own-regulated.