基于CB2调控UHMWPE颗粒诱导松动假体-骨界面成骨细胞增殖与分化

Periprosthetic osteolysis remains the most common causes of failure of total joint arthroplasty, frequently resulting in implant loosening and the need for revision surgery. This intriguing process is triggered by biological reaction of the key cells such as osteoclasts and osteoblasts located in the peri-implant bone to wear particles generated from articulating surfaces of prosthesis. Recently, there has been increasing interest in the role that cannabinoid receptors play in the regulation of bone remodeling. We have demonstrated that cannabinoid receptor 2 (CB2) is highly expressed in the osteolytic tissue induced by wear particles, and CB2 signaling pathway plays a critical role in RANK-RANKL mediated osteclastogenesis. Blockage of CB2 can markedly reduce wear particle induced osteolysis in a murine air pouch model. However, the role of CB2 in osteoblast in the presence of wear particles is not yet well understood. In this project, we decided to investigate the effect of CB2 in wear particle-induced osteoblast differentiation and osteoblast-osteoclast cooperation, using primary osteoblast cells derived from mouse calvaria and mouse spleen-derived hematopoietic cells, respectively. Furthermore, we also investigate the role of CB2 on Ultra-high-molecular-weight polyethylene particle (UHMWPE)-induced osteolysis in a murine murine UHMWPE prosthesis model. The aim of this study was to clarify the relationship between CB2 and wear particle-induced osteoblast function, and provide a promising therapeutic target for treating or preventing aseptic loosening.

无菌性松动（AL）是人工关节置换最常见的并发症，也是限制假体使用寿命的关键因素，至今尚未有效解决。已知AL是磨损颗粒引起的成骨细胞（OB）活性降低、破骨细胞（OC）活性增强的病理过程。最近，本课题组率先证实内源性大麻素Ⅱ型受体（cannabinoid receptor 2, CB2）在磨损颗粒诱导的骨溶解局部高表达，抑制CB2能有效地减少成熟OC数量，减轻骨溶解；然而，CB2与骨溶解局部OB活性降低的关系尚不明确。本课题拟利用细胞和小鼠UHMWPE假体松动模型，重点探讨：①CB2在OB负荷UHMWPE颗粒后对OB增殖、分化的影响及机制；②UHMWPE诱导条件下CB2对OB和OC"cross-talk"的调控作用；③CB2对UHMWPE诱导小鼠假体松动局部骨形成减少的影响及分子机理。通过本研究阐明CB2与UHMWPE颗粒诱导OB功能降低的关系，为人工关节AL的防治提供新的思路和作用靶点。

无菌性松动（aseptic loosening，AL）是多因素作用的复杂病变，其中磨损颗粒引起的破骨细胞（osteoclast，OC）性骨吸收增加和成骨细胞（osteoblast，OB）性骨形成减少是其显著特征。最近，本课题组率先证实内源性大麻素Ⅱ型受体（cannabinoid receptor 2，CB2）在磨损颗粒诱导的骨溶解局部高表达，抑制CB2能有效地减少成熟OC数量，减轻骨溶解；然而，CB2与骨溶解局部OB活性降低的关系尚不明确。本课题研究发现超高分子聚乙烯（UHMWPE）颗粒能够抑制OB增殖与分化，并且对CB2有负向调控作用，JWH133通过活化CB2能增强UHMWPE颗粒环境下OB成骨能力；进一步研究发现BMP/Smad信号通路介导了CB2调控的成骨细胞分化，阻断BMP/Smad信号通路，JWH133促成骨细胞分化能力明显受到抑制；同时，本课题研究发现CB2通过调控RANKL/OPG信号通路间接抑制UHMWPE颗粒引起的OC活化。我们的研究表明CB2对磨损颗粒诱导的OB成骨功能降低有至关重要的作用，为以CB2为靶点研究AL的治疗药物奠定了基础。