Hippo/TAZ调控破骨细胞分化维持骨量的效应和机制研究

The imbalance between the bone formation carried out by osteoblasts and the bone resorption mediated by osteoclasts leads to osteoporosis. We have reported that TAZ, a key molecule of Hippo signaling pathway, plays an important role in the process of osteoblast differentiation（MAT SCI ENG C, 2016）. However, the effects and mechanisms on osteoclast differentiation regulated by Hippo/TAZ remain unknown. Our preliminary experiments found that the mice with TAZ global knockout, as well as osteoclast-conditional knockout, presented osteoporosis phenotype, and TAZ inhibited osteoclast differentiation. Furthermore, Hippo signaling pathway was up-regulated by RANKL, a key molecule in osteoclast differentiation, while TAZ interacted with the osteoclastic cytokine NFATc2, and inhibited its activity. Therefore, we hypothesize that: Hippo/TAZ regulates the osteoclast differentiation via down-regulating the activity of NFATc2, to regulate bone homeostasis. Based on our preliminary researches, this project aims to systematically investigate the effects and the molecule mechanism of Hippo/TAZ on osteoclast differentiation, and its role in homeostasis using the gene knockout mice model and in vitro cell model, as well as clinical specimens from osteoporosis patients, in order to provide evidences of pathogenesis and potential target of precise treatment for osteoporosis.

成骨细胞介导的骨形成与破骨细胞介导的骨吸收之间的失衡会导致骨质疏松。TAZ是Hippo信号中的关键分子，我们研究报道了Hippo/TAZ对间充质干细胞成骨分化的调控（MAT SCI ENG C, 2016），但Hippo/TAZ调控破骨细胞分化的效应和机制却不得而知。本项目前期研究发现：TAZ全身性敲除和破骨细胞中条件性敲除的小鼠均呈骨质疏松表型；TAZ抑制破骨细胞分化，且破骨分化关键分子RANKL能激活Hippo信号；而TAZ能与破骨分化相关因子NFATc2相互作用并抑制其活性。基于此，我们提出假说：在骨量维持中，Hippo/TAZ通过下调NFATc2活性而抑制破骨细胞分化。本课题拟在此基础上，利用基因敲除小鼠模型和体外细胞模型，结合骨质疏松患者标本，系统研究Hippo/TAZ在调控破骨分化中的作用，并阐明其确切的分子机制，以丰富骨代谢平衡的理论，并为骨质疏松的精准治疗提供潜在靶点。

骨质疏松是一种常见的骨骼系统慢性疾病，通常伴有骨质疏松骨折等致残和致死性并发症，严重威胁老年人健康。骨质疏松症是一种溶骨性疾病，通常与破骨细胞过度形成有关。转录辅激活子PDZ结合基序（TAZ）是Hippo信号通路的关键下游效应器；研究表明其参与骨稳态的调节。然而，TAZ在破骨细胞中的确切作用尚未确定。在这项研究中，我们证明：骨质疏松中，TAZ表达下调，表明TAZ与骨质疏松具有相关性。TAZ的全身敲除和破骨细胞特异性敲除导致低骨量表型通过激活了破骨细胞形成，体外破骨细胞形成试验进一步证实了TAZ在破骨细胞的形成中的作用。此外TAZ抑制了RANKL诱导的破骨细胞形成，而TAZ的沉默降低了破骨细胞的形成。机制上来说，TAZ与TGF激活激酶1（TAK1）结合并相互抑制，最终抑制了NF-κB信号传导，抑制破骨细胞分化。综上所述，我们的研究结果证明了TAZ在骨质疏松症破骨细胞形成中的重要作用及其潜在的作用机制, 为骨质疏松的治疗提供了潜在靶点。