Cartilage lesions in degenerative osteoarthritis (OA) are involved with pathological microenvironmental alterations induced by inflammatory macrophages, and apoptotic and/or hypertrophic chondrocytes. However, current non-operative therapies for cartilage repair in OA can rarely achieve long-term and satisfactory outcomes. This study aims to evaluate a newly developed squid type II collagen (SCII) for repairing OA-induced cartilage lesions. Our in vitro data show that SCII induces M2 polarization of macrophages, and activates macrophages to express pro-chondrogenic genes (TGF-β and IGF), which greatly improves the microenvironment around chondrocytes to produce type II collagen and glycosaminoglycan. In addition, glycine in SCII activates glycine receptors on inflammatory chondrocytes to decrease intracellular calcium concentration, leading to effective inhibition of chondrocyte apoptosis and hypertrophy. The in vitro effects of SCII are further confirmed in vivo. In a rat model of OA, SCII increases the ratio of M2 macrophages, elevates the levels of pro-chondrogenic cytokines (TGF-β1 and TGF-β3) in synovial fluid, and inhibits chondrocyte apoptosis and MMP13 production. Our findings show that SCII immunomodulates M2 activation of macrophages to skew the local OA microenvironment towards a pro-chondrogenic atmosphere, and promotes cartilage repair under inflammatory condition. It shows great potential for SCII to be a novel biomaterial for cartilage repair in OA.

退化性骨关节炎（OA）中的软骨病变与炎症性巨噬细胞以及凋亡和/或肥大性软骨细胞诱导的病理性微环境改变有关。然而，目前用于OA的软骨修复的非手术疗法很少能获得长期令人满意的结果。这项研究旨在评估一种新开发的鱿鱼II型胶原蛋白（SCII），用于修复OA诱导的软骨损伤。我们的体外数据显示，SCII诱导巨噬细胞M2极化，并激活巨噬细胞表达促软骨形成基因（TGF-β和IGF），从而极大地改善了软骨细胞周围的微环境，从而产生II型胶原和糖胺聚糖。此外，SCII中的甘氨酸激活炎症性软骨细胞上的甘氨酸受体，从而降低细胞内钙浓度，从而有效抑制软骨细胞凋亡和肥大。在体外SCII的效果进一步证实在体内。在OA大鼠模型中，SCII增加了滑膜液中M2巨噬细胞的比例，升高了促软骨细胞因子（TGF-β1和TGF-β3）的水平，并抑制了软骨细胞的凋亡和MMP13的产生。我们的发现表明，SCII免疫调节巨噬细胞的M2活化，使局部OA微环境偏向促软骨形成的气氛，并在炎症条件下促进软骨修复。它显示了SCII成为用于OA软骨修复的新型生物材料的巨大潜力。