INDIAN HEDGEHOG SIGNALING IN OSTEOBLAST DIFFERENTIATION

描述(由申请人提供)：肌肉骨骼医学存在巨大的未得到满足的临床需求。对于严重骨质疏松或骨折修复延迟愈合或不愈合的患者，迫切需要新的策略来促进骨形成和功能的安全。对成骨细胞分化机制的基本了解是开发这种骨增强策略的关键。我们实验室和其他实验室的工作已经确立了刺猬(Hedgehog，HH)家族成员印度刺猬(India Hedgehog，IHH)在软骨内骨形成过程中对成骨细胞分化、软骨细胞发育和软骨血管形成的重要调节作用--软骨内骨形成是指导骨骼生长和骨折修复的成骨过程。然而，尽管已知转录激活物和抑制物的Gli家族(Gli1-Gli3)共同介导哺乳动物的HH信号转导，但尚不清楚哪种Gli或何种形式(激活物和抑制物)负责骨骼中IHH的各种不同功能。此外，HH信号在成人骨内稳态和再生中的作用尚未阐明。在这个项目的前一个资助周期中，通过利用小鼠遗传学，我们确定了Gli3-主要是被IHH信号拮抗的抑制物-在控制软骨细胞增殖和成熟中的关键作用。有趣的是，我们发现IHH通过独立于Gli3抑制子的机制来调节成骨细胞和骨骼血管的发育；这一发现促使我们假设，IHH在成骨细胞形成和软骨血管形成中的作用需要另一个效应器，很可能是Gli2的激活形式。在目前的方案中，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形成中的作用。此外，我们还将测试HH信号在成年小鼠骨骼稳态和骨折愈合中的潜在作用。公共卫生相关性：肌肉骨骼医学存在巨大的未得到满足的临床需求。需要新的策略来安全地促进骨质疏松和骨折修复中的骨形成。Hedgehog(HH)信号通路是控制胚胎成骨细胞发育的关键途径，为骨合成代谢药物的开发提供了一条很有前途的靶向途径。这一建议旨在阐明HH控制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。本研究的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.