Interaction of Rab3D and Tctex-1 is required for bone resorption through the regulation of post-TGN vesicle trafficking

破骨细胞是负责骨组织分解吸收的多核细胞。破骨细胞数量和/或活性升高是许多使人衰弱的骨科相关疾病的主要标志，包括骨质疏松症、关节炎、骨癌和无菌性松动。其中，骨质疏松症在西方社会是一种地方性疾病，估计每2名女性和每3名男性中就有1人在其一生中经历过骨折。人们普遍认为，含有骨破坏酶的载体囊泡的运输对破骨细胞的骨吸收至关重要。尽管囊泡运输已被证明与微管（细胞骨架）有关，但囊泡和微管相互作用的分子机制在很大程度上是未知的。我们发现了一种新的囊泡运输分子Rab3D与微管结合蛋白Tctex-1之间的相互作用。我们认为，破骨细胞中Rab3D与Tctex-1的结合对于小泡与微管的相互作用以及破骨细胞功能至关重要。该项目的重点是通过分析这种相互作用在破骨细胞介导的骨吸收中的重要性来进一步证实我们的假设。该项目的预期结果是：1)rab3d介导的囊泡运输通过微管网络定向；2) Rab3D和texx -1的相互作用对于Rab3D介导的囊泡转运到微管的耦合至关重要；3) rab3d - txt -1相互作用的破坏可能会损害骨吸收。因此，了解调节破骨细胞囊泡运输的分子机制可能使我们能够开发新的策略来特异性地靶向和抑制骨组织的破坏。

Osteoclasts are multinucleated cells responsible for the breakdown-resorption of bone tissue. Elevated osteoclast numbers and-or activities is a major hallmark of a number of debilitating Orthopaedic-related diseases including osteoporosis, arthritis, bone cancer and aseptic loosening. Among these, osteoporosis is endemic in Western society with an estimated 1 in 2 women and 1 in 3 men sustaining a fracture in their lifetime. It is well accepted that the transport of carrier vesicles containing bone destructive enzymes is critical for bone resorption by osteoclasts. Although vesicle transport has been shown to be associated with microtubules (the cells skeleton), the molecular mechanisms responsible for vesicle and microtubule interaction are largely unknown. We have identified a novel interaction between Rab3D, a vesicle transport molecule, with Tctex-1, a microtubule-binding protein. We propose that the binding of Rab3D to Tctex-1 in osteoclasts is essential for the interaction of vesicles with microtubules and, hence, osteoclast function. The focus of this project is to further confirm our hypothesis by analysing the importance of this interaction in osteoclast-mediated bone resorption. The anticpated outcomes of the proposed project are: 1) Rab3D-mediated vesicle transport is directed via the microtubule network; 2) Interaction between Rab3D and Tctex-1 is cruical for the coupling of Rab3D-mediated vesicle transport to the microtubules; and 3)Disruption of the Rab3D-Tctex-1 interaction may impair bone resorption. Understanding the molecular mechanisms which regulate osteoclastic vesicle trafficking might therefore enable us to develop new strategies to specifically target and inhibit breakdown of bone tissue.