Synovial Cell Cross-talk with Cartilage Plays a Major Role in the Pathogenesis of Osteoarthritis. Synovial Cell Cross-talk with Cartilage Plays a Major Role in the Pathogenesis of Osteoarthritis

We elucidated the molecular cross-talk between knee articular cartilage and paired synovium in n=3 individuals with knee osteoarthritis using the powerful tool of single-cell RNA-sequencing. Multiple cell types were identified based on profiling of 10,640 synoviocytes and 26,192 chondrocytes (11,579 chondrocytes from the diseased medial vs 14,613 chondrocytes from the relatively non-diseased lateral tibial plateau): 12 distinct synovial cell types and 7 distinct articular chondrocyte phenotypes from matched tissues. Intact cartilage was enriched for homeostatic and hypertrophic chondrocytes, while damaged cartilage was enriched for prefibro- and fibro-, regulatory, reparative and prehypertrophic chondrocytes. A total of 61 cytokines and growth factors were predicted to regulate the 7 chondrocyte cell phenotypes. Based on production by >1% of cells, 55% of the cytokines were produced by synovial cells (39% exclusive to synoviocytes and not expressed by chondrocytes) and their presence in osteoarthritic synovial fluid confirmed. The synoviocytes producing IL-1beta (a classic pathogenic cytokine in osteoarthritis), mainly inflammatory macrophages and dendritic cells, were characterized by co-expression of surface proteins corresponding to HLA-DQA1, HLA-DQA2, OLR1 or TLR2. Strategies to deplete these pathogenic intra-articular cell subpopulations could be a therapeutic option for human osteoarthritis. Overall design: We performed single-cell transcriptomic analysis on OA knee joint tissues to systematically identify cell types and states within human osteoarthritic (OA) synovium and matched cartilage as well as determined regulators of these articular chondrocyte phenotypes.

本研究借助单细胞RNA测序（single-cell RNA-sequencing）这一强力研究工具，阐明了3名膝关节骨关节炎患者的膝关节关节软骨与配对滑膜之间的分子交叉对话。研究基于对10640个滑膜细胞（synoviocytes）和26192个软骨细胞（chondrocytes）的转录组分析（其中病变内侧胫骨平台软骨细胞11579个，相对未病变外侧胫骨平台软骨细胞14613个），从配对组织中鉴定出12种不同的滑膜细胞类型与7种不同的关节软骨细胞表型。完整软骨富集稳态型和肥大型软骨细胞，而受损软骨则富集前纤维型、纤维型、调节型、修复型以及前肥大型软骨细胞。本研究共预测到61种细胞因子（cytokines）与生长因子可调控这7种软骨细胞表型。基于细胞占比>1%的表达情况，55%的细胞因子由滑膜细胞产生（其中39%仅在滑膜细胞中表达，软骨细胞不表达），且该类细胞因子在骨关节炎滑液中的存在已得到验证。分泌IL-1β（骨关节炎经典致病细胞因子）的滑膜细胞主要为炎症性巨噬细胞与树突状细胞，其特征为共表达HLA-DQA1、HLA-DQA2、OLR1或TLR2等表面蛋白。清除这类致病关节内细胞亚群的策略，或可成为人类骨关节炎的潜在治疗方案。研究设计概述：本研究对骨关节炎膝关节组织开展单细胞转录组分析，以系统鉴定人类骨关节炎滑膜与配对软骨内的细胞类型与状态，并明确调控上述关节软骨细胞表型的关键因子。