Arthritis and Regenerative Medicine Laboratory, Aberdeen Centre for Arthritis and Musculoskeletal Health, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
Institute of Musculoskeletal Medicine, University Hospital Munster, Munster, Germany.
Ann Rheum Dis. 2020 Dec;79(12):1625-1634. doi: 10.1136/annrheumdis-2020-218350. Epub 2020 Sep 22.
Osteophytes are highly prevalent in osteoarthritis (OA) and are associated with pain and functional disability. These pathological outgrowths of cartilage and bone typically form at the junction of articular cartilage, periosteum and synovium. The aim of this study was to identify the cells forming osteophytes in OA.
Fluorescent genetic cell-labelling and tracing mouse models were induced with tamoxifen to switch on reporter expression, as appropriate, followed by surgery to induce destabilisation of the medial meniscus. Contributions of fluorescently labelled cells to osteophytes after 2 or 8 weeks, and their molecular identity, were analysed by histology, immunofluorescence staining and RNA in situ hybridisation. mice and mice crossed with multicolour reporter mice were used for identification and clonal tracing of mesenchymal progenitors. Mice carrying , , , , or were crossed with tdTomato reporter mice to lineage-trace chondrocytes and stem/progenitor cell subpopulations.
Articular chondrocytes, or skeletal stem cells identified by , or expression, did not give rise to osteophytes. Instead, osteophytes derived from -expressing stem/progenitor cells in periosteum and synovium that are descendants from the -expressing embryonic joint interzone. Further, we show that -expressing progenitors in periosteum supplied hybrid skeletal cells to the early osteophyte, while -expressing progenitors from synovial lining contributed to cartilage capping the osteophyte, but not to bone.
Our findings reveal distinct periosteal and synovial skeletal progenitors that cooperate to form osteophytes in OA. These cell populations could be targeted in disease modification for treatment of OA.
骨赘在骨关节炎（OA）中非常普遍，与疼痛和功能障碍有关。这些软骨和骨的病理性赘生物通常形成在关节软骨、骨膜和滑膜的交界处。本研究的目的是确定 OA 中形成骨赘的细胞。
使用荧光遗传细胞标记和追踪小鼠模型，用他莫昔芬诱导报告基因表达，然后进行内侧半月板不稳定手术。通过组织学、免疫荧光染色和 RNA 原位杂交分析 2 或 8 周后荧光标记细胞对骨赘的贡献及其分子特征。使用 和 与多色 报告小鼠杂交的小鼠来鉴定和克隆追踪间充质祖细胞。携带 、 、 、 或 的小鼠与 tdTomato 报告小鼠杂交，以追踪软骨细胞和干细胞/祖细胞亚群的谱系。
关节软骨细胞或通过 、 或 表达鉴定的骨骼干细胞不会产生骨赘。相反，骨赘来源于骨膜和滑膜中表达 的干细胞/祖细胞，这些细胞是来自表达 的胚胎关节间充质区的后代。此外，我们还表明，骨膜中表达 的祖细胞为早期骨赘提供了混合骨骼细胞，而滑膜衬里中表达 的祖细胞则有助于覆盖骨赘的软骨，但不参与骨的形成。
我们的发现揭示了在 OA 中形成骨赘的独特的骨膜和滑膜骨骼祖细胞。这些细胞群体可能成为 OA 治疗中疾病修饰的靶点。
