Transcriptional mechanisms of steroid hormone action in the skeleton
Our laboratory is focused upon the molecular mechanisms whereby vitamin D, the sex steroids, and other systemic hormones regulate the production as well as cellular activity of bone-forming osteoblasts and bone-resorbing osteoclasts. These two cell types act in concert both to maintain skeletal integrity and to provide vertebrate organisms with minerals such as calcium and phosphorus, and their coordinated and balanced actions are essential to these processes. We seek a detailed understanding of the functional role of each of these hormones in normal skeletal biology as well as their potentially therapeutic role in such diseases as arthritis, osteoporosis, and osteolytic diseases associated with metastatic breast and prostate cancer.
A long-term area of interest has been in the actions of vitamin D. Vitamin D is known to play an important role in skeletal homeostasis, functioning both to stimulate bone formation as well as bone resorption. We have shown that these actions are mediated by a specific receptor that is localized to the nucleus of target cells and which functions as a transcription factor following activation by its hormonal vitamin D ligand. Our research led to the molecular cloning of this factor and elucidation of its regulation and mechanism of action. Current studies seek to extend our knowledge of how this interesting receptor molecule functions to regulate transcription and to identify vitamin D regulated genes that mediate osteoblast and osteoclast function.
A more recent area of interest is in the molecular actions of the sex steroids. Aside from their reproductive roles, the sex steroids estrogen and androgen exert bone protective activities. As a consequence, loss of these hormones during the aging process or following menopause leads to a dramatic loss of bone mineral and an increased risk of fracture. We have shown that both estrogens and androgens function through their nuclear receptors to limit the production of the bone resorbing osteoclasts through a direct action that suppresses osteoclast differentiation. Current studies are focused on understanding both this cellular differentiation process as well as the molecular mechanisms utilized by estrogen to block this important event. These studies involve the use of DNA microarrays to identify the regulatory genes that participate in the differentiation process. Our studies are likely to lead to a better understanding of the pathways that regulate osteoclast formation and to the identification of new estrogenic species with greater bone protective properties.
Left Panel (20X): Large multinucleated osteoclasts (bold arrows) are formed in vitro from tiny mononuclear precursor cells (dashed arrow). Right Panel (10X): Dark stained bone resorption tracks/pits created by the functional osteoclasts seen in the left panel.