Merlin通过联调Hippo与WNT通路影响成骨细胞分化和骨代谢的机制研究

研究成骨细胞分化的分子调控机制对于理解骨代谢疾病的致病机理至关重要。WNT和Hippo信号通路在骨代谢调控中扮演重要的角色。Merlin是Hippo上游的衔接蛋白，与β-catenin也存在潜在的相互作用，因此我们推测Merlin可能参与成骨细胞分化和骨密度的调控。我们前期构建了间充质干细胞Merlin条件性敲除小鼠和Merlin敲低的成骨前体细胞系，发现Merlin是成骨分化的关键调控因子，其缺失同时抑制了Hippo与WNT信号通路。成骨细胞分化不同阶段Hippo的功能仍有争议，Hippo与WNT协作机制尚不明确。本项目将利用条件性敲除小鼠模型研究Merlin在成骨分化的不同阶段的作用，探讨Merlin联调Hippo与WNT的分子机制，并探索Merlin及其复合体作为骨密度调控靶点的可能性。本项目可为成骨细胞中Hippo与WNT联调机制提供新的理论依据，为骨疾病提供新靶点。

Studying molecular mechanism underlying osteoblast (OB) differentiation is important for understanding the pathogenesis of metabolic bone diseases. A bunch of studies support that WNT and Hippo signaling play important roles in OB differentiation and bone metabolism. Merlin is an upstream adaptor protein of Hippo signaling, also with potential direct interaction with β-catenin. Thus we predicted that Merlin might play an important role in OB differentiation and skeletal metabolism. We found that Merlin is highly expressed in trabecular bone tissue while its role in bone tissue is unclear. We generated Mesenchyme stem cell (MSC) specific Merlin conditional knockout (CKO) mice and revealed that Merlin plays dispenaible roles in OB differentiation and skeletal development. We also found that Merlin deletion results in YAP up-regulation and inhibition of β-catenin activity in OB. However, questions remains to be studied: ① Role of Merlin at different stage of osteoblast differentiation;② how Merlin regulates the crosstalk between WNT and Hippo in bone; ③ possibility of Merlin and its functional complex to be the target of osteoporosis treatment. In the proposal, we will generate MSC-specific, early OB-specific and late OB-specific Merlin CKO mice, to study the role of Merlin in OB differentiation and skeletal metabolism, at different stages of OB development. We will study the molecular mechanism underlying Merlin regulating OB development, as well as Merlin regulating crosstalk between Hippo and WNT signaling pathways. We are also proposing to explore the components and upstream in the Merlin complex, and the possibility to target Merlin-Hippo signaling for osteoporosis treatment. Our study will reveal the molecular mechanism underlying Merlin regulating OB differentiation and skeletal metabolism, as well as Hippo and WNT crosstalk. Our study might also provide novel therapeutic target for skeletal diseases.