During the last decade, our view on the skeleton as a mere solid physical support structure has been transformed, as bone emerged as a dynamic, constantly remodeling tissue with systemic regulatory functions including those of an endocrine organ. Reflecting this remarkable functional complexity, distinct classes of humoral and intracellular regulatory factors have been shown to control vital processes in the bone. Among these regulators,
nuclear receptors (NRs) play fundamental roles in bone development, growth, and maintenance. NRs are
DNA-binding
transcription factors that act as intracellular transducers of the respective
ligand signaling pathways through modulation of expression of specific sets of cognate target genes. Aberrant NR signaling caused by receptor or
ligand deficiency may profoundly affect bone health and compromise skeletal functions.
Ligand dependency of NR action underlies a major strategy of therapeutic intervention to correct aberrant NR signaling, and significant efforts have been made to design novel synthetic NR
ligands with enhanced beneficial properties and reduced potential negative side effects. As an example,
estrogen deficiency causes bone loss and leads to development of
osteoporosis, the most prevalent skeletal disorder in postmenopausal women. Since administration of natural
estrogens for the treatment of
osteoporosis often associates with undesirable side effects, several
synthetic estrogen receptor
ligands have been developed with higher therapeutic efficacy and specificity. This review presents current progress in our understanding of the roles of various
nuclear receptor-mediated signaling pathways in bone physiology and disease, and in development of advanced NR
ligands for treatment of common skeletal disorders.