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，对大多数患者来说，髋部骨折是失去行动能力、失去独立性、住院治疗和继发性医疗发病率和死亡率的恶性循环的第一步。髋部骨折一年内，50%的患者在没有辅助的情况下无法行走，25%需要长期护理，20%死亡。一个有效的调节因素是物理负荷（Krahl et al. 1994），然而细胞感知机制已被证明是难以捉摸的。我们的实验室是第一个证明最近描述的骨细胞初级纤毛似乎在这一过程中起主要作用的实验室之一（Malone et al. 2007）。初级纤毛是单个的单细胞延伸，几乎每个人都有，但其功能仍然难以捉摸。作为骨细胞的机械传感器，这些细胞器与其他先前确定的机制协同作用来调节骨代谢。我们在这里的贡献预计是阐明初级纤毛微结构域在骨细胞机械转导中的作用，并确定所涉及的细胞内信号传导机制。这一贡献是重要的，因为它是一个关键的初始步骤，将催化连续的

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.