Modest Effects of Osteoclast-Specific ERa Deletion after Skeletal Maturity

Estrogen regulates bone mass in women and men, but the underlying cellular mechanisms of estrogen action on bone remain unclear. Although both estrogen receptor (ER)alpha and ER beta are expressed in bone cells, ERa is the dominant receptor for skeletal estrogen action. Previous studies using either global or cell-specific ERa deletion provided important insights, but each of these approaches had limitations. Specifically, either high circulating sex steroid levels in global ERa knockout mice or the effects of deletion of ERa during growth and development in constitutive cell-specific knockout mice have made it difficult to clearly define the role of ERa in specific cell types in the adult skeleton. We recently generated and characterized mice with tamoxifen-inducible ERa deletion in osteocytes driven by the 8-kb Dmp1 promoter (ER alpha Delta Ocy mice), revealing detrimental effects of osteocyte-specific ERa deletion on trabecular bone volume (similar to 20.1%) and bone formation rate (similar to 18.9%) in female, but not male, mice. Here, we developed and characterized analogous mice with inducible ERa deletion in osteoclasts using the Cathepsin K promoter (ER alpha Delta Ocl mice). In a study design identical to that with the previously described ER alpha Delta Ocy mice, adult female, but not male, ER alpha Delta Ocl mice showed a borderline (similar to 10.2%, p = 0.084) reduction in trabecular bone volume, no change in osteoclast numbers, but a significant increase in serum CTx levels, consistent with increased osteoclast activity. These findings in ER alpha Delta Ocl mice differ from previous studies of constitutive osteoclast-specific ER alpha deletion, which led to clear deficits in trabecular bone and increased osteoclast numbers. Collectively, these data indicate that in adult mice, estrogen action in the osteocyte is likely more important than via the osteoclast and that ERa deletion in osteoclasts from conception onward has more dramatic skeletal effects than inducible osteoclastic ER alpha deletion in adult mice. (c) (C) 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.