Evaluation of the nuclear receptor Retinoid Acid Receptor related Receptor alpha (RORalpha) as a novel regulator of osteoclastogenesis in rheumatoid arthritis and osteoporosis

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Rheumatoid arthritis (RA) and osteoporosis are bone diseases with increasing frequencies. Both diseases are characterized by increased differentiation of monocytic cells into osteoclasts leading to enhanced bone resorption. Although treatment of both diseases has been improved, many patients with RA and osteoporosis still suffer from severe functional impairment and both diseases are associated with a high socioeconomic burden. In our first experiments, we showed that the retinoid-related orphan receptor alpha (ROR alpha, also known as NR1F1) is induced during inflammation-induced osteoclastogenesis. Inactivation of ROR alpha prevented osteoclastogenesis and decreased bone resorption both in vitro and in the mouse model of serum-transfer induced arthritis. With the current proposal, we aim to further characterize the role of ROR alpha on osteoclastogenesis and inflammation. We will evaluate the effect of targeting ROR alpha in mice overexpressing tumor necrosis factor alpha (TNF tg mice) and in ovarectomy-induced osteoporosis using recently developed selective inhibitors and mice expressing conditional alleles of ROR alpha. We will also analyze, whether lentiviral overexpression of ROR alpha increases osteoclastogenesis and osteoclast mediated bone resorption in vitro and in vivo. Finally, we aim to identify the molecular pathways, by which ROR alpha regulates inflammation, osteoclastogenesis and osteoclast mediated bone resorption. Given the availability of selective and potent inhibitors of ROR alpha, our studies may have direct therapeutic implications.