Estrogens are key hormones in bone remodeling. Estrogen deficiency in postmenopausal women frequently leads to osteoporosis, the most common skeletal disorder. Osteoporotic bone loss is the result of high bone turnover in which bone resorption outpaces bone formation. This imbalance can be ameliorated with bioavailable estrogens. Estrogens primarily act by regulating gene transcription via estrogen receptors (ERα, ERα). In mice, though ERα appears to be the major estrogen receptor, neither bone loss nor high bone turnover is detectable in ERα knock-out females. This unexpected maintenance of bone mass in female mutants is presumed to be due to unphysiologically elevated levels of other osteoprotective hormones, like androgens. Systemic defects in the hypothalamus caused by ER inactivation appear to impair the negative feedback system of hormone production. This leads to an excess in estrogen precursors, notably androgens. Thus, irrespective of the accumulating clinical and basic research data on the osteoprotective actions of estrogens, the molecular basis of this osteoprotection in females remains elusive. In this study [1], the authors report a critical role for ERα in mediating estrogen-dependent bone maintenance in female mice.

In mice, ERα were selectively ablated in differentiated osteoclasts. Females, but not males, exhibited trabecular bone loss, similar to the osteoporotic bone phenotype in postmenopausal women. Further, estrogens induced apoptosis (programmed cell death) and upregulation of Fas ligand (FasL), a proapoptotic mediator expression in osteoclasts of the trabecular bones of wild type but not transgenic mice lacking ERα in their osteoclasts. The expression of ERα was also required for the induction of apoptosis in cultured osteoclasts.

These results support a model in which estrogen regulates the life span of mature osteoclasts via the induction of the Fas/FasL system, thereby providing an explanation for the osteoprotective function of estrogens. However, osteoporosis involves also a deficit in bone formation, which is an important therapeutic target.

1. Nakamura T et al. Cell. 2007;130:811-823.