Ⅰ型BMP受体BMPR1B介导的BMP信号与WNT信号交叉对话在骨重塑中的作用机理研究

骨重塑对骨生长发育至关重要。已知BMP信号和WNT信号交叉对话参与了骨重塑，而且Ⅰ型BMP受体BMPR1A和ACVR1介导的BMP信号通过与WNT信号通路相互作用而负性调控骨量。我们前期通过在小鼠体内敲除另一种Ⅰ型BMP受体Bmpr1b基因，发现小鼠体内骨量减少；进一步发现WNT信号通路的抑制基因Sost和Dkk1表达下降，推测BMPR1B介导的BMP信号通过与WNT信号交叉对话正性调控骨量。为此，拟利用所建立的基因敲除小鼠模型，采用影像学、组织形态测量学和分子生物学等方法，研究Bmpr1b基因敲除后对成骨细胞和破骨细胞分化及其相互作用对骨形成与骨吸收的影响；进一步采用细胞生物学、细胞化学和分子生物学等方法，研究Bmpr1b基因敲除后，BMP和WNT信号通路改变同破骨细胞和成骨细胞分化与功能的关系，阐明BMPR1B介导的BMP信号通路在骨重塑中的作用机理，为防治骨吸收破坏性疾病奠定基础。

Bone remodeling is critical to bone development and growth. It is known that BMP-WNT signaling cross-talk participates in bone remodeling. It is also known that BMP signaling mediated by type I BMP receptor, BMPR1A or ACVR1, negatively regulates bone mass through communication with WNT signaling. Our preliminary data showed that deletion of Bmpr1b gene, another BMP type I receptor, decreased bone mass. Further, we found that the expression of WNT signaling inhibitors Sost and Dkk1 was decreased in Bmpr1b knockout mice. We hypothesized that BMP signaling mediated by BMPR1B positively regulates bone mass through communication with WNT signaling. To test this hypothesis, we used the Bmpr1b knockout mouse model, and will study bone formation and bone resorption mediated by osteoblast and osteoclast and their communication using micro-CT, histomorphometry and molecular biology; we will evaluate the differentiation of osteoclast and osteoblast, as well as the molecular changes in BMP signaling and WNT signaling. The objective is to clarify the molecular mechanisms of BMP signaling mediated by BMPR1B in bone remodeling. Our findings will lay the foundation for the prevention and treatment of bone diseases.