前期研究发现：抑制磷脂酶Cγ1（PLCγ1）促进了成骨细胞分化与矿化。同时，依赖PLCγ1的成骨细胞功能调控间接调节了软骨细胞基质合成。藉此提出：靶向早期OA软骨下骨成骨细胞内PLCγ1，既能调控成骨细胞功能，还可通过成骨细胞与软骨细胞间crosstalk调节关节软骨基质稳态，进而从骨软骨单位(osteochondral unit)整体水平干预早期OA病理进程。但PLCγ1如何调控OA成骨细胞功能，依赖于PLCγ1的成骨细胞功能调控如何调节软骨基质稳态等尚不明确。本项目拟探讨以下科学问题：（1）PLCγ1如何调控成骨细胞功能、干预OA早期软骨下骨病理进程？（2）PLCγ1是否通过调节内质网应激，改变自噬实现对成骨细胞功能的调控？（3）依赖于PLCγ1的成骨细胞功能调控如何通过骨软骨单位内细胞间crosstalk调节软骨基质稳态、干预OA早期软骨病理进程？进而达到骨软骨单位水平防治OA的目的

Osteoarthritis (OA) is characterized by chondrocyte death and cartilage matrix degradation. However, therapeutic agents that modulate chondrocyte activities have been successful in arresting or slowing the progression of joint pathology only in animal models of OA. It could be partly attributed to the complexity of joint anatomy and OA pathological processes in patients with OA. Multiple therapeutic approaches for OA indicate that subchondral bone, one of components in osteochondral unit, is involved in OA pathological progression. Additionally, based on the crosstalk between subchondral bone and articular cartilage, some effective therapeutic approaches targeting subchondral bone could trigger articular chondrocyte metabolism and vice versa. Our preliminary experimental results demonstrated that the inhibition of phosphoinositide-specific phospholipase Cγ1 (PLCγ1) could promote differentiation and mineralization of OA osteoblast. Moreover, PLCγ1-driven regulation in OA osteoblast could affect the matrix synthesis of chondrocyte. Therefore, we hypothesize that increased mineralization via targeting PLCγ1 in OA osteoblast could not only promote its mineralization capacity to reduce bone resorption, but also maintain the phenotype and matrix homeostasis of OA chondrocytes to protect against OA cartilage destruction, with the implication of intervening the pathological progression at the level of osteochondral unit at early stage of OA. To testify the hypothesis, we firstly investigate how PLCγ1 modulates the differentiation and mineralization of OA osteoblast in cell and animal models of OA, and decipher the signal pathways involved in PLCγ1-mediated mineralization in OA osteoblast. Secondly, we focus on the regulatory mechanism of PLCγ1 associated with endoplasmic reticulum stress (ERS) and autophagy in OA osteoblast. At last, we examine the effect of PLCγ1-mediated mineralization of OA osteoblast on the phenotype and matrix homeostasis of chondrocyte via cell co-culture system, as well as OA animal model. These experiments might testify our hypothesis and make it possible to prevent or treat OA at the level of osteochondral unit.