INDIAN HEDGEHOG SIGNALING IN OSTEOBLAST DIFFERENTIATION

描述（由申请人提供）：在肌肉骨骼医学中存在大量未满足的临床需求。迫切需要新的策略来促进严重骨质疏松症或骨折修复中出现延迟愈合或不愈合的患者的骨形成和功能安全。对控制成骨细胞分化的机制的基本理解对于这种骨增强策略的发展至关重要。我们的实验室和其他研究人员已经确定，刺猬家族成员印度刺猬（Ihh）是软骨内成骨过程中成骨细胞分化、软骨细胞发育和软骨血管形成的重要调节因子，而成骨过程指导骨骼生长和骨折修复。然而，尽管已知Gli家族（Gli1-Gli3）的转录激活因子和抑制因子共同介导哺乳动物的Hh信号，但尚不清楚哪种Gli或哪种形式（激活因子与抑制因子）负责骨骼中Ihh的每种不同功能。此外，Hh信号在成人骨稳态和再生中的作用尚未阐明。在本项目的上一个资助周期中，我们利用小鼠遗传学方法确定了Gli3在控制软骨细胞增殖和成熟中的关键作用，Gli3主要是一种被Ihh信号拮抗的抑制因子。有趣的是，我们发现Ihh通过独立于Gli3抑制因子的机制调节成骨细胞和骨骼血管的发育；这一发现促使我们假设一种额外的效应物，最有可能是Gli2的激活物形式，是介导Ihh在成骨细胞发生和软骨血管形成中的作用所必需的。在目前的提案中，我们将测试Gli2激活剂在ihh介导的成骨细胞分化和骨骼血管化中的作用。此外，我们将测试Hh信号在成年小鼠骨稳态和骨折愈合中的潜在作用。公共卫生相关性：在肌肉骨骼医学中存在大量未满足的临床需求。在骨质疏松症和骨折修复中，需要新的策略来安全地促进骨形成。Hedgehog （Hh）信号已被证实是调控胚胎成骨细胞发育的关键通路，为骨合成代谢药物的发育提供了一个有希望的靶点通路。本研究旨在阐明Hh调控成骨细胞分化的分子机制，以及Hh信号在成人骨稳态和骨折修复中的潜在作用。本研究结果将为开发新型骨增强药物提供分子框架。

DESCRIPTION (provided by applicant): Tremendous unmet clinical needs exist in musculoskeletal medicine. Novel strategies are urgently needed to promote bone formation and function safely in patients with severe osteoporosis or experiencing delayed-union or nonunion in fracture repair. A fundamental understanding of mechanisms governing osteoblast differentiation is critical for the development of such bone-enhancing strategies. Work from our laboratory and others has firmly established Indian hedgehog (Ihh), a member of the Hedgehog (Hh) family, as an essential regulator for osteoblast differentiation, chondrocyte development and cartilage vascularization during endochondral bone formation - the osteogenic process that directs both skeletal growth and bone fracture repair. However, although it is known that the Gli family (Gli1-Gli3) of transcriptional activators and repressors collectively mediate Hh signaling in mammals, it is not clear which Gli or what form (activator versus repressor) is responsible for each of the diverse functions of Ihh in the skeleton. Moreover, the role of Hh signaling in bone homeostasis and regeneration in the adult has not been elucidated. In the previous funding cycle of this project, by employing murine genetics we established the critical role of Gli3 - predominantly a repressor antagonized by Ihh signaling - in control of chondrocyte proliferation and maturation. Intriguingly, we uncovered that Ihh regulates both osteoblast and skeletal vascular development via mechanisms independent of the Gli3 repressor; this finding prompted us to hypothesize that an additional effector, most probably the activator form of Gli2, is required for mediating the role of Ihh in osteoblastogenesis and in cartilage vascularization. In the current proposal we will test the role of Gli2 activator in Ihh-mediated osteoblast differentiation and skeletal vascularization. In addition, we will test the potential roles of Hh signaling in bone homeostasis and fracture healing in adult mice. PUBLIC HEALTH RELEVANCE: Tremendous unmet clinical needs exist in musculoskeletal medicine. Novel strategies are required to safely promote bone formation in osteoporosis and bone fracture repair. Hedgehog (Hh) signaling has been established to be a key pathway controlling osteoblast development in the embryo, providing a promising target pathway for development of bone anabolic agents. This proposal is designed to elucidate the molecular mechanism through which Hh controls osteoblast differentiation, as well as the potential roles of Hh signaling in bone homeostasis and fracture repair in the adult. Research results from this study will provide a molecular framework for developing novel bone-enhancing pharmaceutics.