SR-A neutralizing antibody: potential drug candidate for ameliorating osteoclastogenesis in rheumatoid arthritis
SR-A neutralizing antibody: potential drug candidate for ameliorating osteoclastogenesis in rheumatoid arthritis
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SR-A 中和抗体：改善类风湿性关节炎破骨细胞生成的潜在候选药物
DOI：
10.1093/cei/uxac010
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发表时间：
2022
影响因子：
4.6
通讯作者：
Fanlei Hu
中科院分区：
文献类型：
--
作者：
Yang Xie;Xiang Jiang;Ping Wang;Xi Zheng;Jing Song;Mingxin Bai;Yundi Tang;Xiangyu Fang;Yuan Jia;Zhanguo Li;Fanlei Hu
抽象的。类风湿关节炎(RA)是一种以增生性滑膜炎为特征的自身免疫性疾病，伴有软骨和骨骼的恶化。破骨细胞(OCs)是RA骨破坏的积极参与者。尽管有了很大的进步，但目前大多数RA的治疗策略对骨破坏的效果有限。巨噬细胞清道夫受体A(SR-A)是一类参与骨代谢和OC分化的模式识别受体。最近，我们的研究揭示了SR-A在RA诊断和发病机制中的关键作用。在这里，我们进一步证明，血清SR-A水平与RA患者的骨破坏呈正相关。抗SR-A中和抗体显著抑制RA患者的OC分化和体外骨吸收，但在健康人中无此作用，抑制OC特异性基因的表达，如酒石酸抗性酸性磷酸酶(TRAP)、组织蛋白酶K(CTSK)和基质金属蛋白酶-9(MMP-9)。在胶原诱导性关节炎(CIA)小鼠的体外实验中也看到了类似的结果。此外，抗SR-A中和抗体还能进一步改善CIA小鼠体内和体外破骨细胞的形成，并降低血清C末端端肽和IL-6水平，显示出潜在的保护作用。这些结果表明，用抗SR-A中和抗体阻断SR-A可能为RA的骨破坏提供了一种有前途的治疗策略。
Abstract. Rheumatoid arthritis (RA) is an autoimmune disease characterized by proliferative synovitis with deterioration of cartilage and bone. Osteoclasts (OCs) are the active participants in the bone destruction of RA. Although with great advances, most current therapeutic strategies for RA have limited effects on bone destruction. Macrophage scavenger receptor A (SR-A) is a class of pattern recognition receptors (PRRs) involved in bone metabolism and OC differentiation. More recently, our study revealed the critical role of SR-A in RA diagnosis and pathogenesis. Here, we further demonstrated that serum SR-A levels were positively correlated with bone destruction in patients with RA. Anti-SR-A neutralizing antibodies significantly inhibited OC differentiation and bone absorption in vitro in patients with RA, but not in healthy individuals, dampening the expression of OC-specific genes such as tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), and matrix metalloproteinase-9 (MMP-9). Similar results were also seen in collagen-induced arthritis (CIA) mice in vitro. Moreover, the anti-SR-A neutralizing antibody could further ameliorate osteoclastogenesis in vivo and ex vivo in CIA mice, accompanied by decreased serum levels of C-terminal telopeptide and IL-6, exhibiting potential protective effects. These results suggest that blockade of SR-A using anti-SR-A neutralizing antibodies might provide a promising therapeutic strategy for bone destruction in the RA.