The Role of Ror-Beta in the Skeleton

Ror-Beta 在骨骼中的作用

• 批准号: 8936575
• 负责人: David G Monroe
• 金额: $ 34.98万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8936575
• 关键词: Affect; Age; Age-Related Bone Loss; Aging; Anabolism; Antibodies; Attention; Biology; Bone Marrow; Bone Resorption; Cells; Clinical; Clinical Trials; Data; Development; Elderly; FDA approved; Fracture; Gene Targeting; Homeostasis; Human; In Vitro; Laboratories; Lead; Life; Ligand Binding Domain; Measures; MicroRNAs; Molecular; Mus; Nuclear; Orphan; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Pathway interactions; Patients; Pattern; Population; Process; Publishing; Regulation; Repression; Retinoic Acid Receptor; Risk; Role; Signal Transduction; Skeleton; Techniques; Testing; Therapeutic; Transgenic Mice; aged; base; beta catenin; bone; bone loss; bone mass; combat; cost; in vitro activity; in vivo; inhibitor/antagonist; interest; mouse model; novel; novel therapeutic intervention; osteoblast differentiation; osteoclastogenesis; osteogenic; osteoprogenitor cell; overexpression; public health relevance; receptor; skeletal; success; transcription factor

 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.

 描述（由申请人提供）：骨质疏松症是一种常见的临床疾病，其特征是骨量低，增加了老年人群脆性骨折的风险。由于骨质疏松患者的骨形成明显受损，因此更全面地了解调节骨形成的基本分子机制可能会导致新疗法的开发。然而，唯一FDA批准的合成代谢疗法是PTH，其疗效有限。因此，鉴定影响骨形成的新分子途径对于开发对抗骨质疏松症的化合物至关重要。我们已经确定了核转录因子Rorbal作为一个新的球员在调节骨量。在成骨细胞分化过程中，Rorbal表达减少，在衰老过程中，在骨髓源性骨祖细胞库中表达增加。与此相反，Rorthrin的过度表达抑制成骨细胞分化。在小鼠中缺失Rorbal会导致整个衰老过程中骨量的显著增加，这是由于骨形成的增加伴随着骨吸收的减少。我们还发现，Roraldehyde抑制Runx2和Wnt途径，这两条重要途径对骨形成有积极影响。总的来说，这些数据建立了Rorbal作为一种新的和重要的转录因子在调节骨稳态。我们建议进一步探讨Rorbol作用的机制，特别强调Runx2和Wnt活性的调节。在目标1中，我们将明确地确定骨祖细胞衍生的Rorthin在老化骨中的作用。我们假设，在骨祖细胞中特异性缺失Rorbal蛋白将在衰老过程中保持骨量，而在衰老、骨质疏松小鼠中诱导性缺失Rorbal蛋白将抑制甚至逆转骨丢失。在 目的2研究罗丹明对骨祖细胞Runx2活性的抑制作用。我们发展了一种新的技术，从小鼠骨髓中分离和研究高度富集的骨祖细胞，而不需要体外培养。我们还将研究一组新的罗勒调节的miRNA在控制Runx2活性中的作用。在目标3中，我们将研究罗丹明在抑制Wnt活性中的作用。我们假设Rorbal的缺失增加了Wn活性，导致骨祖细胞库的扩大。此外，我们有证据表明，Roraldehyde也抑制Opg，破骨细胞生成的负调节因子，这将在本提案中进行测试。因此，罗丹明作为一种新的骨量调节剂的作用的功能表征将促进我们对骨稳态控制的基本过程的理解，并为罗丹明特异性抑制剂作为合成代谢性骨质疏松症治疗的开发提供重要信息。