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

类风湿性关节炎(RA)和骨质疏松症是发病率越来越高的骨病。这两种疾病的特征都是单核细胞向破骨细胞分化增加，导致骨吸收增强。尽管这两种疾病的治疗方法已经有所改善，但许多RA和骨质疏松患者仍存在严重的功能障碍，这两种疾病都与较高的社会经济负担有关。在我们的第一个实验中，我们证明了维甲酸相关的孤儿受体α(RORα，也称为NR1F1)是在炎症诱导的破骨细胞形成过程中诱导的。在体外和血清转移诱导的关节炎小鼠模型中，RORα的失活阻止了破骨细胞的形成，并减少了骨吸收。通过目前的建议，我们的目标是进一步表征RORα在破骨细胞形成和炎症中的作用。我们将使用最近开发的选择性抑制剂和表达RORα条件等位基因的小鼠来评估靶向RORα在高表达肿瘤坏死因子α的小鼠(TNFTG小鼠)和卵巢切除所致的骨质疏松中的效果。我们还将分析，在体外和体内，慢病毒过表达RORα是否会增加破骨细胞的生成和破骨细胞介导的骨吸收。最后，我们的目标是确定RORα调控炎症、破骨细胞形成和破骨细胞介导骨吸收的分子途径。鉴于选择性和有效的RORα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.