Background:Posttraumatic osteoarthritis (PTOA) arises secondarily to joint trauma and is driven by catabolic inflammatory pathways. Alpha-2-macroglobulin (α2M) is a naturally occurring proteinase inhibitor found in human serum and synovial fluid that binds proteases as well as proinflammatory cytokines involved in the pathogenesis of PTOA.Purpose:(1) To investigate the therapeutic potential of intra-articular α2M injections during the acute stages of PTOA by inhibiting inflammatory pathways driven by the cytokines expressed by the synovium in a large preclinical Yucatan minipig model and (2) to determine if 3 intra-articular α2M injections have greater chondroprotective effects compared with 1 intra-articular injection.Study Design:Controlled laboratory study.Methods:A total of 48 Yucatan minipigs were randomized into 4 groups (n = 12 each): (1) modified intra-articular drilling (mIAD) and saline (mIAD + saline), (2) mIAD and 1 intra-articular α2M injection (mIAD +α2M-1), (3) mIAD and 3 α2M injections (mIAD +α2M-3), and (4) sham control. Surgical hindlimbs were harvested at 15 weeks after surgery. Cartilage degeneration, synovial changes, inflammatory gene expression, and matrix metalloproteinase levels were evaluated. Gait asymmetry was measured before and after surgery using a pressure-sensing walkway system.Results:Macroscopic lesion areas and microscopic cartilage degeneration scores were lower in the mIAD +α2M-1 and mIAD +α2M-3 groups compared with the mIAD + saline group ( P < .05) and similar to those in the sham group ( P > .05). Synovial membrane scores of the mIAD +α2M-1 and mIAD +α2M-3 groups were lower than that of the mIAD + saline group ( P < .05) and higher than that of the sham group ( P < .05). Interleukin-1 beta, nuclear factor kappa B, and tumor necrosis factor alpha mRNA expression in the synovium and matrix metalloproteinase-1 levels in synovial fluid were significantly lower in the mIAD +α2M-1 and mIAD +α2M-3 groups compared with the mIAD + saline group ( P < .05). No significant differences were observed between the mIAD +α2M-1 and mIAD +α2M-3 groups for all measured outcomes. There were early changes in gait ( P < .05) between preoperative and postoperative time points for the mIAD + saline, mIAD +α2M-1, and mIAD +α2M-3 groups that normalized by 15 weeks.Conclusion:Animals receiving early α2M treatment exhibited less cartilage damage, milder synovitis, and lower inflammation compared with animals with no α2M treatment. These results exemplify the early anti-inflammatory effects of α2M and provide evidence that intra-articular α2M injections may slow the progression of PTOA.Clinical Relevance:In patients presenting with an acute joint injury, an early intervention with α2M may have the potential to reduce cartilage degeneration from catabolic pathways and delay the development of PTOA.

中文翻译：

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α-2-巨球蛋白在尤卡坦小型猪模型中通过改良关节内钻孔抑制炎症通路来减轻创伤后骨关节炎软骨损伤


背景： 创伤后骨关节炎 （PTOA） 继发于关节创伤，由分解代谢炎症途径驱动。α-2-巨球蛋白 （α2M） 是一种天然存在的蛋白酶抑制剂，存在于人血清和滑液中，可结合参与 PTOA 发病机制的蛋白酶和促炎细胞因子。目的： （1） 通过抑制大型临床前尤卡坦小型猪模型中滑膜表达的细胞因子驱动的炎症通路，研究关节内注射 α2M 在 PTOA 急性期的治疗潜力，以及 （2） 确定 3 次关节内注射 α2M 是否比 1 次关节内注射具有更大的软骨保护作用。研究设计： 对照实验室研究。方法： 将 48 头尤卡坦小型猪随机分为 4 组 （n=12 每组）：（1） 改良关节内钻孔 （mIAD） 和生理盐水 （mIAD + 盐水），（2） mIAD 和 1 次关节内 α2M 注射 （mIAD +α2M-1），（3） mIAD 和 3 次 α2M 注射 （mIAD +α2M-3），以及 （4） 假对照。手术后 15 周收获手术后肢。评估软骨变性、滑膜变化、炎症基因表达和基质金属蛋白酶水平。使用压力感应走道系统在手术前后测量步态不对称性。结果： mIAD +α2M-1 和 mIAD +α2M-3 组肉眼病变面积和微观软骨变性评分低于 mIAD + 生理盐水组 （ P < .05），与假手术组相似 （P > .05）。mIAD +α2M-1 和 mIAD +α2M-3 组滑膜评分低于 mIAD + 生理盐水组 （ P < .05），高于假手术组 （P < .05）。 与 mIAD + 生理盐水组相比，mIAD +α2M-1 和 mIAD +α2M-3 组滑膜中白细胞介素-1 β、核因子 kappa B 和肿瘤坏死因子 α mRNA 的表达和滑液中基质金属蛋白酶-1 水平显著降低 （ P < .05）。对于所有测量结果，mIAD +α2M-1 和 mIAD +α2M-3 组之间未观察到显著差异。mIAD + 生理盐水、 mIAD +α2M-1 和 mIAD +α2M-3 组术前和术后时间点步态早期变化 （P < .05） 在 15 周时恢复正常。结论： 与未接受 α2M 治疗的动物相比，接受早期 α2M 治疗的动物表现出较少的软骨损伤、较轻的滑膜炎和较低的炎症。这些结果体现了 α2M 的早期抗炎作用，并提供了关节内注射 α2M 可以减缓 PTOA 进展的证据。临床相关性： 在急性关节损伤患者中，α2M 的早期干预可能有可能减少分解代谢途径的软骨变性并延缓 PTOA 的发展。