McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, AB, Canada.
Department of Cell Biology and Anatomy, University of Calgary, Calgary, AB, Canada.
Cell Death Dis. 2022 May 18;13(5):470. doi: 10.1038/s41419-022-04919-1.
Aggrecan is a critical component of the extracellular matrix of all cartilages. One of the early hallmarks of osteoarthritis (OA) is the loss of aggrecan from articular cartilage followed by degeneration of the tissue. Mesenchymal progenitor cell (MPC) populations in joints, including those in the synovium, have been hypothesized to play a role in the maintenance and/or repair of cartilage, however, the mechanism by which this may occur is unknown. In the current study, we have uncovered that aggrecan is secreted by synovial MPCs from healthy joints yet accumulates inside synovial MPCs within OA joints. Using human synovial biopsies and a rat model of OA, we established that this observation in aggrecan metabolism also occurs in vivo. Moreover, the loss of the "anti-proteinase" molecule alpha-2 macroglobulin (A2M) inhibits aggrecan secretion in OA synovial MPCs, whereas overexpressing A2M rescues the normal secretion of aggrecan. Using mice models of OA and cartilage repair, we have demonstrated that intra-articular injection of aggrecan into OA joints inhibits cartilage degeneration and stimulates cartilage repair respectively. Furthermore, when synovial MPCs overexpressing aggrecan were transplanted into injured joints, increased cartilage regeneration was observed vs. wild-type MPCs or MPCs with diminished aggrecan expression. Overall, these results suggest that aggrecan secreted from joint-associated MPCs may play a role in tissue homeostasis and repair of synovial joints.
聚集蛋白聚糖是所有软骨细胞外基质的关键成分。骨关节炎 (OA) 的早期标志之一是软骨中聚集蛋白聚糖的丢失，随后组织发生退化。关节中的间充质祖细胞 (MPC) 群体，包括滑膜中的 MPC，被假设在软骨的维持和/或修复中发挥作用，但是，其发生的机制尚不清楚。在本研究中，我们发现健康关节的滑膜 MPC 会分泌聚集蛋白聚糖，但在 OA 关节的滑膜 MPC 中会积累聚集蛋白聚糖。通过使用人滑膜活检和 OA 大鼠模型，我们证实了这种聚集蛋白聚糖代谢的观察结果也发生在体内。此外，“抗蛋白酶”分子α-2 巨球蛋白 (A2M) 的丢失会抑制 OA 滑膜 MPC 中聚集蛋白聚糖的分泌，而 A2M 的过表达则可以挽救聚集蛋白聚糖的正常分泌。通过使用 OA 和软骨修复的小鼠模型，我们已经证明向 OA 关节内注射聚集蛋白聚糖可以分别抑制软骨退化和刺激软骨修复。此外，当过表达聚集蛋白聚糖的滑膜 MPC 被移植到受损关节中时，与野生型 MPC 或聚集蛋白聚糖表达减少的 MPC 相比，观察到增加的软骨再生。总的来说，这些结果表明，关节相关 MPC 分泌的聚集蛋白聚糖可能在滑膜关节的组织稳态和修复中发挥作用。
