Primary cilia as mechanotransducers in bone

描述(申请人提供)：髋部骨折是骨质疏松症最具破坏性的结果，对大多数患者来说，髋部骨折是失去行走能力、丧失独立性、住院以及继发医疗发病率和死亡率的螺旋式下降的第一步。在髋部骨折的一年内，50%的患者将无法在没有帮助的情况下行走，25%的患者将需要长期护理，20%的患者将因身体负荷而死亡(Krahl等人)。然而，细胞传感机制已被证明是难以捉摸的。我们的实验室是第一批证明最近描述的骨细胞初级纤毛似乎在这一过程中发挥重要作用的实验室之一(Malone等人)。2007)。初级纤毛是单个孤立子细胞的延伸，几乎由身体中的每一个人拥有，但其功能仍然难以捉摸。作为骨细胞的机械传感器，这些细胞器与其他先前发现的调节骨代谢的机制协同作用。我们的贡献是阐明初级纤毛微域在骨细胞机械转导中所起的作用，并确定所涉及的细胞内信号机制。这一贡献意义重大，因为它是一个关键的初始步骤，将催化 这项研究有望带来新的药物治疗策略，在分子水平上模拟机械负荷。该项目的长期目标是确定初级纤毛如何促进骨骼对机械负荷的感知和反应能力。这个应用程序的总体目标是确定它们的确切功能角色。为了实现这一目标，我们将确定机械激活的骨细胞纤毛内和细胞内信号通路(SA1)，骨细胞初级纤毛是否调节成骨细胞成骨(SA2)，并建立骨细胞初级纤毛转导在机械诱导骨形成(SA3)中的作用。在项目结束时，我们希望证明初级纤毛作为骨细胞的机械传感器，阐明了涉及的分子传感器和信号通路，并至少在原则上证明了体内和体外。预防骨质疏松症将显著提高生活质量，减少发病率，降低医疗费用。一个附带的好处将有助于形成初级纤毛作为细胞外信号感知和骨和其他细胞类型整合的纽带的图景。

DESCRIPTION (provided by applicant): Hip fractures are the most devastating result of osteoporosis, and for most patients, the first step in downward spiral of lost ambulation, lost independence, institutionalization, and secondary medical morbidity and mortality. Within one year of hip fracture, 50% of patients will be unable to walk without assistance, 25% will require long-term care, and 20% will have died One potent regulator is physical loading (Krahl et al. 1994), however the cellular sensing mechanism has proven to be elusive. Our laboratory is among one of the first demonstrating that the recently described osteocyte primary cilium appears to play a major role in this process (Malone et al. 2007). Primary cilia are single solitar cellular extensions, possessed by virtually every in the body, but whose function remains elusive. As osteocyte mechanosensors, these organelles acting synergistically with other previously identified mechanisms to regulate bone metabolism. Our contribution here is expected to be elucidating the role that primary cilia microdomains play in osteocyte mechanotransduction and to identify the intracellular signaling mechanism involved. This contribution is significant because it is a critical initial step that will catalyze a continuum of research expected to lead to novel pharmacologic therapeutic strategies that mimic mechanical loading at a molecular level. The long-term goal of this project is to determine how primary cilia contribute to bone's ability to sense and respond to mechanical loading. The overall objective of this application is to identify their precise functional role. We will achieve this objective determining the mechanically activated osteocyte intraciliary and intracellular signaling pathways (SA1), whether osteocyte primary cilia regulate osteoblastic osteogenesis (SA2), and establish the role of osteocyte primary cilia transduction in mechanically induced bone formation (SA3). At the conclusion of the project we hope to have demonstrated that primary cilia act as osteocyte mechanosensors, elucidated the molecular sensor and signaling pathway involved, and demonstrated, at least in principle, in vivo and in vitro. Prevention of osteoporosis will resut in a dramatic increase in quality of life, reduce morbidity, and reduce health care costs. A collateral benefit will be contributing to the emerging picture of primary cilia as a nexus of extracellular signal sensing and integration in bone and other cell types.