Primary cilia as mechanotransducers in bone

描述（由申请人提供）：髋部骨折是骨质疏松症最具破坏性的结果，对于大多数患者来说，是失去截肢、失去独立性、机构化和继发性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%的患者将死亡。一个有效的调节器是物理负荷（Krahl等人，1994），然而细胞传感机制已被证明是难以捉摸的。我们的实验室是最早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（马龙等人，2007）。初级纤毛是单个孤立的细胞延伸，几乎每个人都有，但其功能仍然难以捉摸。作为骨细胞的机械感受器，这些细胞器与其他先前确定的机制协同作用，以调节骨代谢。我们的贡献有望阐明初级纤毛微结构域在骨细胞力学转导中的作用，并确定所涉及的细胞内信号转导机制。这一贡献意义重大，因为它是一个关键的初始步骤，将催化一系列 研究预期导致新的药理学治疗策略，在分子水平上模拟机械负荷。这个项目的长期目标是确定初级纤毛如何有助于骨骼感知和响应机械负荷的能力。本应用程序的总体目标是确定其确切的功能作用。我们将实现这一目标，确定机械激活的骨细胞内纤毛和细胞内信号通路（SA 1），骨细胞初级纤毛是否调节成骨细胞成骨（SA 2），并建立骨细胞初级纤毛转导在机械诱导骨形成（SA 3）的作用。在该项目的结论，我们希望已经证明，初级纤毛作为骨细胞mechanosensors，阐明了分子传感器和信号通路参与，并证明，至少在原则上，在体内和体外。预防骨质疏松症将导致生活质量的显著提高，降低发病率，并减少医疗费用。一个附带的好处将有助于初级纤毛作为细胞外信号传感和整合在骨和其他细胞类型的联系的新的图片。

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.