Nuclear Receptors in Bone Physiology and Diseases

Abstract

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.

International Union of Basic and Clinical Pharmacology. XCVII. G Protein–Coupled Estrogen Receptor and Its Pharmacologic Modulators

“…Although estrogens are recognized predominantly for their function in female mammalian reproduction and the development of secondary sex characteristics, namely uterine and mammary effects, they also play important roles in almost every physiologic system of the body (Edwards, 2005) in both women and men (Lombardi et al, 2001;Finkelstein et al, 2013). As pharmaceutical targets, estrogens and their varied antagonists have been particularly important in contraception (Benagiano et al, 2006) and breast cancer therapy (Jensen and Jordan, 2003), with an increasing appreciation of their therapeutic value in the nervous (McEwen et al, 2012), immune (Cunningham and Gilkeson, 2011), vascular (Knowlton and Lee, 2012), skeletal (Imai et al, 2013), and endocrine systems . For decades, the actions of estrogen(s) were thought to be mediated by a single estrogen receptor first identified in the 1960s (Jensen and Jacobson, 1962;Jensen and DeSombre, 1973), that is, until the discovery of a second highly homologous estrogen receptor in 1996 (Kuiper et al, 1996), whereupon the first estrogen receptor was renamed estrogen receptor a (ERa) and the new receptor ERb.…”

The myImageAnalysis Project: A Web-Based Application for High-Content Screening

“…It has become clear that controlling the expression level, subcellular distribution, and even the subnuclear distribution of TFs are all key regulatory mechanisms to control gene expression. 17,18 Traditional biochemical methods for understanding each of these mechanisms are often time-consuming, fail to capture the cellular heterogeneity in a population, and are not easily amendable to high-throughput screening.…”

Development of the External Genitalia and Their Sexual Dimorphic Regulation in Mice

“…As mentioned earlier, AGD and perineum muscle formation are also effective indicators of masculinization. The musculoskeletal system is sensitive to the action of androgen as documented in the effect of synthetic androgens on bone density and muscle mass [Imai et al, 2013]. It has been suggested that AR is present within the muscles and is involved in postnatal growth of BC/ LA muscles through AR-positive satellite cells [Chen et al, 2005].…”