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

风湿性关节炎（RA）和骨质疏松症是骨疾病的频率增加。这两种疾病的特征在于单核细胞向破骨细胞的分化增加，导致骨吸收增强。虽然这两种疾病的治疗已经得到改善，但许多患有RA和骨质疏松症的患者仍然患有严重的功能障碍，并且这两种疾病都与高社会经济负担相关。在我们的第一个实验中，我们发现类维生素A相关孤儿受体α（ROR α，也称为NR1F1）在炎症诱导的破骨细胞生成过程中被诱导。ROR α的失活在体外和血清转移诱导的关节炎小鼠模型中均阻止破骨细胞生成并降低骨吸收。通过目前的提议，我们的目标是进一步表征ROR α在破骨细胞生成和炎症中的作用。我们将使用最近开发的选择性抑制剂和表达ROR α条件等位基因的小鼠，评估在过表达肿瘤坏死因子α的小鼠（TNF tg小鼠）和卵巢切除术诱导的骨质疏松症中靶向ROR α的作用。我们还将分析，是否ROR α的慢病毒过表达增加破骨细胞生成和破骨细胞介导的骨吸收在体外和体内。最后，我们的目标是确定ROR α调节炎症，破骨细胞生成和破骨细胞介导的骨吸收的分子途径。鉴于ROR α的选择性和有效抑制剂的可用性，我们的研究可能具有直接的治疗意义。

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.