Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China; Academy of Orthopedics, Guangdong Province, Guangzhou 510630, China; Department of Orthopedics, Qinghai Provincial People's Hospital, Xining 810007, China.
Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China; Academy of Orthopedics, Guangdong Province, Guangzhou 510630, China.
Int Immunopharmacol. 2018 Dec;65:522-530. doi: 10.1016/j.intimp.2018.09.038. Epub 2018 Nov 6.
This study aims to investigate the effect of enriched plasma cells on the production of inflammatory cytokines and development of osteoarthritis (OA) in mice with B-cell-specific conditional deletion of the tuberous sclerosis 1 gene (TSC1). OA was induced by destabilization of the medial meniscus (DMM) in mice with TSC1 disruption in B cells (CD19-TSC1) and in littermate control mice (CON). The effects of DMM and incidence of OA were evaluated histologically, mRNA levels of inflammatory cytokines were detected by polymerase chain reaction, and serum cytokine levels were detected by enzyme-linked immunosorbent assay. Deletion of TSC1 caused constitutive activation of mechanistic target of rapamycin complex 1 mTORC1 in B cells. CON mice subjected to DMM exhibited a severe OA phenotype with increased inflammatory cytokines in B cells, serum, and the synovial membrane. Importantly, inflammatory cytokine production was also increased in B cells from the spleen of CD19-TSC1 conditional KO mice, but the OA phenotype was significantly elevated in conditional KO mice after DMM surgery compared with CON mice, as indicated by more severe articular cartilage destruction, increased protein expression of matrix metalloproteinase-13 and mRNA of type X collagen in the articular cartilage, decreased mRNA expression of type II collagen in the articular cartilage, and increased inflammatory cytokines in serum and the synovial membrane. The results demonstrate that inflammatory cytokine synthesis by B cells was enriched in CD19-TSC1 conditional KO mice, and this enhanced synthesis of inflammatory cytokines accelerated the incidence of OA.
本研究旨在探讨富含浆细胞对 B 细胞特异性条件性敲除结节性硬化症 1 基因（TSC1）小鼠炎症细胞因子产生和骨关节炎（OA）发展的影响。通过破坏 B 细胞中的 TSC1（CD19-TSC1）和同窝对照小鼠（CON）中的 TSC1 来诱导 OA（DMM）。通过组织学评估 DMM 的效果和 OA 的发生率、聚合酶链反应检测炎症细胞因子的 mRNA 水平以及酶联免疫吸附试验检测血清细胞因子水平来检测。TSC1 的缺失导致 B 细胞中雷帕霉素复合物 1 mTORC1 的组成性激活。CON 小鼠接受 DMM 后，B 细胞、血清和滑膜中的炎症细胞因子增加，表现出严重的 OA 表型。重要的是，CD19-TSC1 条件性 KO 小鼠脾脏中的 B 细胞中也增加了炎症细胞因子的产生，但与 CON 小鼠相比，DMM 手术后条件性 KO 小鼠的 OA 表型明显升高，如关节软骨破坏更严重、基质金属蛋白酶-13 的蛋白表达增加和关节软骨中 X 型胶原的 mRNA 增加、关节软骨中 II 型胶原的 mRNA 减少以及血清和滑膜中的炎症细胞因子增加。结果表明，B 细胞中炎症细胞因子的合成在 CD19-TSC1 条件性 KO 小鼠中富集，这种炎症细胞因子的合成增强加速了 OA 的发生。
