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.