Estrogen Receptor α36 Mediates a Bone-Sparing Effect of 17β-Estrodiol in Postmenopausal Women

Recently, a membrane-based estrogen receptor (ER), ER-alpha 36, was identified and cloned that transduces membrane-initiated estrogen signaling such as activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway. Here we show that the postmenopausal level of estradiol (E2) induces mitogenic, antiapoptotic, and antiosteogenic effects and proapoptotic effects in postmenopausal osteoblasts and osteoclasts with high levels of ER-alpha 36 expression, respectively. We also found that ER-alpha 36 mediated the effects of postmenopausal-level E-2 on proliferation, apoptosis, and differentiation of osteoblasts through transient activation of the MAPK/ERK pathway, whereas ER-alpha 36-mediated postmenopausal-level E-2 induces apoptosis of osteoclasts through prolonged activation of the MAPK/ERK pathway with the involvement of reactive oxygen species. We also show that the levels of ER-alpha 36 expression in bone are positively associated with bone mineral density but negatively associated with bone biochemical markers in postmenopausal women. Thus the higher levels of ER-alpha 36 expression are required for preserving bone mass in postmenopausal and menopausal women who become osteoporotic if ER-alpha 36-mediated activities are dysregulated. (C) 2011 American Society for Bone and Mineral Research.