Osteoblast‐Like Cells From Estrogen Receptor α Knockout Mice Have Deficient Responses to Mechanical Strain

Osteoblast‐like cells in primary cultures derived from ERα−/− mice do not proliferate in response to mechanical strain, unlike those from their ERα+/+ littermates. ERα−/− cells also lack strain‐related NO production and responsiveness to IGFs. Proliferative responsiveness to strain is rescued by transfection with functional ERα. ERα number or function in bone cells may limit bones' adaptability to mechanical loading. Introduction: In vivo, bones' osteogenic response to mechanical loading involves proliferation of surface osteoblasts. This response is replicated in vitro and involves ERK‐mediated activation of the estrogen receptor (ER) α and upregulation of estrogen response element activity. This proliferative response can be blocked by selective estrogen receptor modulators and increased by transfection of additional ERα. Materials and Methods: We have now investigated the mechanisms of ER involvement in osteoblast‐like cells' early responses to strain by comparing the responses of primary cultures of these cells derived from homozygous ERα knockout (ERKO) mice (ERα−/−) with those from their wildtype (ERα+/+) and heterozygous (ERα+/−) littermates and from ERβ knockout (BERKO) mice (ERβ+/+, ERβ+/−, and ERβ−/−). Results: Whereas ERα+/+, ERα+/−, ERβ+/+, and ERβ−/− cells proliferate in response to a single 10‐minute period of cyclic strain, ERα−/− cells do not. Transfection of fully functional, but not mutant, ERα rescues the proliferative response to strain in these cells. The strain‐related response of ERα−/− cells is also deficient in that they show no increased activity of an AP‐1 driven reporter vector and no strain‐related increases in NO production. Their strain‐related increase in prostacyclin production is retained. They proliferate in response to fibroblast growth factor‐2 but not insulin‐like growth factor (IGF)‐I or IGF‐II, showing the importance of ERα in the IGF axis and the ability of ERα−/− cells to proliferate normally in response to a mitogenic stimulus that does not require functional ERα. Conclusions: These data indicate ERα's obligatory involvement in a number of early responses to mechanical strain in osteoblast‐like cells, including those that result in proliferation. They support the hypothesis that reduction in ERα expression or activity after estrogen withdrawal results in a less osteogenic response to loading. This could be important in the etiology of postmenopausal osteoporosis.