The estrogen receptor's involvement in osteoblasts' response to mechanical strain

The estrogen receptors' role in osteoblasts' proliferative response to mechanical strain was investigated by studying the effect of selective estrogen receptor modulators ICI 182, 780, tamoxifen and raloxifene on the independent and combined effects of 17<IMG WIDTH=9 HEIGHT=24 ALIGN=MIDDLE SRC="/maths/beta.gif">-estradiol, strain and growth factors bFGF and EGF. Estradiol increased [³H]thymidine incorporation in primary cultures of female-derived osteoblasts as did a single period of strain (3,400 <IMG WIDTH=8 HEIGHT=14 ALIGN=MIDDLE SRC="/maths/mu.gif"><IMG WIDTH=4 HEIGHT=7 ALIGN=BOTTOM SRC="/maths/vareps.gif">, 600 cycles, 1Hz, maximum strain rate 23,000<IMG WIDTH=8 HEIGHT=14 ALIGN=MIDDLE SRC="/maths/mu.gif"><IMG WIDTH=4 HEIGHT=7 ALIGN=BOTTOM SRC="/maths/vareps.gif">/s). At 10^-8 M tamoxifen and raloxifene increased basal proliferation but not ICI. At this concentration raloxifene and tamoxifen eliminated, and ICI substantially reduced, the proliferation associated with strain. Both tamoxifen and ICI reduced EGF-induced proliferation but had not effect on that by FGF. That these SERMs should affect proliferation associated with estradiol and EGF, but not that by FGF, was expected since the action of estrogen and EGF involves the ER, whereas that of FGF does not. That SERMs should prevent the proliferative response to strain suggests that strain stimulates proliferation by a mechanism involving the ER.

The extent to which the effects of strain are mediated through the ER was investigated in male-derived osteoblasts. Estrogen, testosterone, 5<IMG WIDTH=7 HEIGHT=7 ALIGN=BOTTOM SRC="/maths/alpha.gif">-dihydrotestosterone all increased proliferation. Strain independently and in combination with estradiol or testosterone significantly increased proliferation. The aromatase inhibitor 4-hydroxyandrostenedione inhibited the testosterone-induced effect suggesting that the effect of testosterone in males is due to estrogen after aromatisation. ICI and tamoxifen inhibited proliferation due to testosterone implicating the involvement of the ER.

The implications of these data to postmenopausal osteoporosis are discussed and future investigations to understand the molecular and cellular mechanisms involved are proposed.