Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK.
Rheumatology & Immuno-Mediated Diseases Research Group (IRIDIS), Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Vigo, Spain.
Cell Biochem Funct. 2024 Apr;42(3):e4012. doi: 10.1002/cbf.4012.
Osteoarthritis (OA) is characterised by the deterioration of cartilage in the joints and pain. We hypothesise that semaphorin-3A (sema-3A), a chemorepellent for sensory nerves, plays a role in joint degradation and pain. We used the mechanical joint loading (MJL) model of OA to investigate sema-3A expression in the joint and examine its association with the development of OA and pain. We also analyse its effect on chondrocyte differentiation using the ATDC5 cell line. We demonstrate that sema-3A is present in most tissues in the healthy joint and its expression increases in highly innervated tissues, such as cruciate ligaments, synovial lining and subchondral bone, in loaded compared to nonloaded control joints. In contrast, sema-3A expression in cartilage was decreased in the severe OA induced by the application of high loads. There was a significant increase in circulating sema-3A, 6 weeks after MJL compared to the nonloaded mice. mRNA for sema-3A and its receptor Plexin A1 were upregulated in the dorsal root ganglia of mice submitted to MJL. These increases were supressed by zoledronate, an inhibitor of bone pain. Sema-3A was expressed at all stages of Chondrocyte maturation and, when added exogenously, stimulated expression of markers of chondrocyte differentiation. This indicates that sema-3A could affect joint tissues distinctively during the development of OA. In highly innervated joint tissues, sema-3A could control innervation and/or induce pain-associated neuronal changes. In cartilage, sema-3A could favour its degeneration by modifying chondrocyte differentiation.
骨关节炎（OA）的特征是关节软骨退化和疼痛。我们假设，轴突导向因子 3A（sema-3A），一种感觉神经的化学排斥物，在关节退化和疼痛中发挥作用。我们使用机械关节加载（MJL）OA 模型来研究关节中的 sema-3A 表达，并研究其与 OA 和疼痛发展的关系。我们还使用 ATDC5 细胞系分析其对软骨细胞分化的影响。我们证明，sema-3A 存在于健康关节的大多数组织中，其表达在高神经支配组织中增加，例如十字韧带、滑膜衬里和软骨下骨，在加载关节中与非加载对照关节相比。相比之下，在高负荷引起的严重 OA 中，软骨中的 sema-3A 表达减少。与非加载小鼠相比，MJL 后 6 周循环 sema-3A 显著增加。MJL 小鼠的背根神经节中 sema-3A 和其受体 Plexin A1 的 mRNA 上调。用唑来膦酸（一种骨痛抑制剂）抑制这些增加。sema-3A 在软骨细胞成熟的所有阶段表达，并且当外源性添加时，刺激软骨细胞分化标志物的表达。这表明，sema-3A 可能在 OA 发展过程中对关节组织产生不同的影响。在高神经支配的关节组织中，sema-3A 可以控制神经支配和/或诱导与疼痛相关的神经元变化。在软骨中，sema-3A 可以通过改变软骨细胞分化来促进其退化。
