The Role of Ror-Beta in the Skeleton

 描述(由申请人提供)：骨质疏松症是一种常见的临床症状，其特征是骨量低，增加了老年人脆性骨折的风险。由于骨质疏松患者的骨形成明显受损，更全面地了解调控骨形成的基本分子机制可能会导致新疗法的发展。然而，FDA唯一批准的合成代谢疗法是甲状旁腺素，其疗效有限。因此，识别影响骨形成的新的分子途径对于开发抗骨质疏松的化合物至关重要。我们发现核转录因子Ror？是一种新的骨量调节因子。在成骨细胞分化过程中，ROR？？的表达减少，而在衰老过程中，骨髓来源的成骨祖细胞库中的ROR？表达增加。相反，过表达的Ror？？抑制成骨细胞分化。在小鼠中，由于骨形成的增加和骨吸收的减少，在整个衰老过程中，由于骨形成的增加和随之而来的骨吸收的减少，Rorç基因的缺失导致骨量显著增加。我们还发现，Ror？？抑制了Runx2和Wnt途径，这是两条积极影响骨形成的重要途径。总而言之，这些数据确立了Rorç作为一种新的和重要的转录因子在骨稳态调节中的作用。我们建议进一步探索Rorç作用的机制，特别强调对Runx2和Wnt活动的调节。在目标1中，我们将明确地确定骨祖细胞衍生的罗氏在骨骼老化中的作用。我们假设，在骨祖细胞中特定缺失的Ror？？将在衰老过程中保存骨量，而在老年骨质疏松小鼠中可诱导的Ror？？缺失将抑制甚至逆转骨丢失。在……里面 目的研究Ror？在抑制骨祖细胞Runx2活性中的作用。我们建立了一种新的技术，无需体外培养，即可从小鼠骨髓中分离和研究高度浓缩的成骨细胞。我们还将研究一组新的由Ror？调节的miRNAs在控制Runx2活性中的作用。在目标3中，我们将研究Ror？？在抑制Wnt活性中的作用。我们假设Rorç的缺失增加了Wn的活性，并导致骨祖细胞库的扩大。此外，我们有证据表明，罗尔也抑制OPG，一种破骨细胞生成的负性调节因子，这将在这项提案中得到测试。因此，对罗伯作为一种新的骨量调节因子的作用进行功能表征将有助于我们理解控制骨内稳态的基本过程，并为开发罗伯特异性抑制剂作为一种合成代谢的骨质疏松症治疗方法提供重要信息。

 DESCRIPTION (provided by applicant): Osteoporosis is a common clinical condition characterized by low bone mass that increases the risk of fragility fractures in the elderly population. Since bone formation is clearly impaired in osteoporotic patients, a more complete understanding of the fundamental molecular mechanisms that regulate bone formation is likely to lead to the development of novel therapies. However, the only FDA approved anabolic therapy is PTH, which has limited efficacy. Therefore, identification of novel molecular pathways which influence bone formation is crucial to the development of compounds to combat osteoporosis. We have identified the nuclear transcription factor Rorß as a novel player in the regulation of bone mass. Rorß expression decreases during osteoblast differentiation and increases in the bone marrow-derived osteoprogenitor pool during aging. In contrast, overexpression of Rorß inhibits osteoblast differentiation. Deletion of Rorß in mice results in significant increases in bone mass throughout aging, due to an increase in bone formation with a concomitant decrease in bone resorption. We have also found that Rorß represses the Runx2 and Wnt pathways, two important pathways that positively influence bone formation. Collectively, these data establish Rorß as a novel and important transcription factor in the regulation of bone homeostasis. We propose to further explore the mechanism of Rorß action with particular emphasis on regulation of both Runx2 and Wnt activities. In Aim 1 we will definitively establish the role of osteoprogenitor-derived Rorß in aging bone. We hypothesize that specific deletion of Rorß in osteoprogenitors will preserve bone mass during aging and that inducible deletion of Rorß in aged, osteoporotic mice will inhibit, or even reverse, bone loss. In Aim 2 we will investigate the role of Rorß in the inhibition of Runx2 activity in osteoprogenitors We have developed a novel technique to isolate and study highly enriched osteoprogenitor cells from mouse bone marrow without the need for in vitro culture. We will also examine the role of a novel set of Rorß-regulated miRNAs in the control of Runx2 activity. In Aim 3, we will examine the role of Rorß in the inhibition of Wnt activity. We hypothesize that loss of Rorß increases Wn activity and results in an expansion of the osteoprogenitor cell pool. Furthermore, we have evidence that Rorß also represses Opg, a negative regulator of osteoclastogenesis, which will be tested in this proposal. Therefore, functional characterization of the role of Rorß as a novel regulator of bone mass will advance our understanding the fundamental processes underlying the control of bone homeostasis, and provide important information for the development of Rorß-specific inhibitors as an anabolic osteoporosis therapy.