Department of Orthopedics, Academy of Orthopedics - Guangdong Province, Orthopedic Hospital of Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
Key Laboratory of Tropical Diseases and Translational Medicine of the Ministry of Education, and Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou, China.
Ann Rheum Dis. 2018 Oct;77(10):1524-1534. doi: 10.1136/annrheumdis-2018-213450. Epub 2018 Jul 10.
To investigate the roles and regulatory mechanisms of synovial macrophages and their polarisation in the development of osteoarthritis (OA).
Synovial tissues from normal patients and patients with OA were collected. M1 or M2-polarised macrophages in synovial tissues of patients with OA and OA mice were analysed by immunofluorescence and immunohistochemical staining. Mice with tuberous sclerosis complex 1 (TSC1) or Rheb deletion specifically in the myeloid lineage were generated and subjected to intra-articular injection of collagenase (collagenase-induced osteoarthritis, CIOA) and destabilisation of the medial meniscus (DMM) surgery to induce OA. Cartilage damage and osteophyte size were measured by Osteoarthritis Research Society International score and micro-CT, respectively. mRNA sequencing was performed in M1 and control macrophages. Mice and ATDC5 cells were treated with R-spondin-2 (Rspo2) or anti-Rspo2 to investigate the role of Rspo2 in OA.
M1 but not M2-polarised macrophages accumulated in human and mouse OA synovial tissue. TSC1 deletion in the myeloid lineage constitutively activated mechanistic target of rapamycin complex 1 (mTORC1), increased M1 polarisation in synovial macrophages and exacerbated experimental OA in both CIOA and DMM models, while Rheb deletion inhibited mTORC1, enhanced M2 polarisation and alleviated CIOA in mice. The results show that promoting the macrophage M1 polarisation leads to exacerbation of experimental OA partially through secretion of Rspo2 and activation of β-catenin signalling in chondrocytes.
Synovial macrophage M1 polarisation exacerbates experimental CIOA partially through Rspo2. M1 macrophages and Rspo2 are potential therapeutic targets for OA treatment.
探讨滑膜巨噬细胞及其极化在骨关节炎（OA）发展中的作用和调控机制。
收集正常患者和 OA 患者的滑膜组织。通过免疫荧光和免疫组织化学染色分析 OA 患者和 OA 小鼠滑膜组织中的 M1 或 M2 极化巨噬细胞。生成 TSC1 或 Rheb 特异性缺失于骨髓谱系的小鼠，并进行关节内注射胶原酶（胶原酶诱导的 OA，CIOA）和内侧半月板不稳定（DMM）手术，以诱导 OA。通过国际骨关节炎研究协会评分和 micro-CT 分别测量软骨损伤和骨赘大小。在 M1 和对照巨噬细胞中进行 mRNA 测序。用 R-spondin-2（Rspo2）或抗 Rspo2 处理小鼠和 ATDC5 细胞，以研究 Rspo2 在 OA 中的作用。
M1 极化但不是 M2 极化的巨噬细胞在人 OA 和鼠 OA 滑膜组织中积聚。骨髓谱系中的 TSC1 缺失持续激活雷帕霉素靶蛋白复合体 1（mTORC1），增加滑膜巨噬细胞中的 M1 极化，并在 CIOA 和 DMM 模型中加剧实验性 OA，而 Rheb 缺失抑制 mTORC1，增强 M2 极化并减轻小鼠的 CIOA。结果表明，促进巨噬细胞 M1 极化通过在软骨细胞中分泌 Rspo2 和激活 β-连环蛋白信号部分导致实验性 OA 的加重。
滑膜巨噬细胞 M1 极化部分通过 Rspo2 加剧实验性 CIOA。M1 巨噬细胞和 Rspo2 是 OA 治疗的潜在治疗靶点。
