Estrogen receptor et in osteocytes regulates trabecular bone formation in female mice

Estrogens are well known steroid hormones necessary to maintain bone health. In addition, mechanical loading, in which estrogen signaling may intersect with the Wnt/beta-catenin pathway, is essential for bone maintenance. As osteocytes are known as the major mechanosensory cells embedded in mineralized bone matrix, osteocyte ER alpha deletion mice (ER alpha(Delta Ocy/Delta Ocy)) were generated by mating ERa floxed mice with Dmp1-Cre mice to determine the role of ER alpha in osteocytes. Trabecular bone mineral density of female, but not male ER alpha(Delta Ocy/Delta Ocy) mice was significantly decreased. Bone formation parameters in ER alpha(Delta Ocy/Delta Ocy) were significantly decreased while osteoclast parameters were unchanged. This suggests that ERot in osteocytes exerts osteoprotective function by positively controlling bone formation. To identify potential targets of ER alpha, gene array analysis of Dmp1-GFP osteocytes sorted by FACS from ER alpha(Delta Ocy/Delta Ocy) and control mice was performed. Gene expression microarray followed by gene ontology analyses revealed that osteocytes from ER alpha(Delta Ocy/Delta Ocy) highly expressed genes categorized in 'Secreted' when compared to control osteocytes. Among them, expression of Mdk and Sostdc1, both of which are Wnt inhibitors, was significantly increased without alteration of expression of the mature osteocyte markers such as Sost and beta-catenin. Moreover, hindlimb suspension experiments showed that trabecular bone loss due to unloading was greater in ER alpha(Delta Ocy/Delta Ocy) mice without cortical bone loss. These data suggest that ERot in osteocytes has osteoprotective functions in trabecular bone formation through regulating expression of Wnt antagonists, but conversely plays a negative role in cortical bone loss due to unloading. Published by Elsevier Inc.