Primary Cilia as Mechanotransducer in Bone

摘要 髋部骨折是骨质疏松症造成的最具破坏性的结果，通常是失去的螺旋式下降的第一步。 行走和独立、制度化和二次医疗发病率和死亡率。在一个范围内 髋部骨折一年，50%的患者将在没有帮助的情况下无法行走，25%的患者将需要长期护理， 而20%的人将会死亡。骨形成的一个强有力的调节因素是物理负荷(Krahl等人。1994年)；然而， 指导机械转导的细胞传感机制已被证明是难以捉摸的。我们的实验室是 首次证明骨细胞初级纤毛在这一过程中起主要作用(Malone等人。 2007)。初级纤毛是一种孤立的细胞延伸，几乎存在于身体的每一个细胞中，但其功能 还没有得到充分的定性。作为骨细胞的机械传感器，这些细胞器与其他 已知的骨代谢调节剂。我们的贡献是阐明初级纤毛微域在 骨细胞的机械转导，并确定涉及的细胞内信号机制。这一贡献 意义重大，因为它催化了一系列研究，导致了新的药物疗法 在分子水平上加强机械负荷。该项目的长期目标是确定主要的 纤毛有助于骨骼机械传感，并利用这一知识开发新的治疗方法。整体而言 这项申请的目的是利用在上一个资助期确定的分子机制来敏化 骨细胞纤毛和确定骨细胞纤毛的特异性治疗靶点。我们将通过以下方式实现这一目标 建立体内骨细胞纤毛疗法(SA1)的潜力，通过以下方式增强骨细胞特异性 分子操纵内睫状体信号系统(SA2)，并确保睫状体策略不会 对骨生物学的不良影响(SA3)。在这个项目结束时，我们期待着贡献潜力 针对骨细胞微域的独特特征以偏向骨形成的药物 不会对正常生理产生不良影响。预防骨质疏松症将显著提高患者质量 改善生活，减少发病率，降低医疗成本。一个附带的好处是将这一知识扩展到 在其他细胞类型中的应用，以开发许多纤毛相关疾病的治疗方法。

Summary Hip fractures are the most devastating result of osteoporosis and often the first step in a downward spiral of lost ambulation and 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 of bone formation is physical loading (Krahl et al. 1994); however, the cellular sensing mechanism directing mechanotransduction has proven to be elusive. Our laboratory is one of the first to demonstrate that the osteocyte primary cilium plays a major role in this process (Malone et al. 2007). The primary cilium is a solitary cellular extension present in virtually every cell in the body, but its function has yet to be fully characterized. As osteocyte mechanosensors, these organelles act synergistically with other known regulators of bone metabolism. Our contribution is to elucidate the primary cilium microdomain’s role in osteocyte mechanotransduction and identify the intracellular signaling mechanisms involved. This contribution is significant because it catalyzes a continuum of research leading to novel pharmacologic therapeutics that potentiate mechanical loading at a molecular level. The long-term goal of this project is to determine how primary cilia contribute to bone mechanosensing and capitalize on this knowledge to develop novel therapies. The overall objective of this application is to exploit the molecular mechanisms identified in the last funding period to sensitize osteocyte primary cilia and identify osteocyte-cilia specific therapeutic targets. We will achieve this objective by establishing the potential of osteocyte cilia therapeutics in vivo (SA1), enhancing osteocyte-specificity through molecular manipulation of the intraciliary signaling system (SA2), and ensuring that ciliary strategies do not have adverse effects on bone biology (SA3). At the conclusion of this project, we expect to contribute potential pharmacologic agents that target unique characteristics of the osteocyte microdomain to bias bone formation without adverse effects to normal physiology. Osteoporosis prevention will dramatically increase patient quality of life, reduce morbidity, and cut health care costs. A collateral benefit will be extending this knowledge to applications in other cell types to develop treatments for numerous cilia-associated diseases.