Blockade of parathyroid hormone-related protein prevents joint destruction and granuloma formation in streptococcal cell wall-induced arthritis
Blockade of parathyroid hormone-related protein prevents joint destruction and granuloma formation in streptococcal cell wall-induced arthritis
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DOI：
10.1002/art.10985
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发表时间：
2003-06-01
影响因子：
--
通讯作者：
Stafford, G
中科院分区：
文献类型：
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作者：
Funk, JL;Chen, J;Stafford, G
目标。目的：探讨甲状旁腺激素相关蛋白(PTHrP)在类风湿关节炎(RA)关节破坏的病理生理机制中的作用。在链球菌细胞壁(SCW)诱导的RA动物模型上检测PTHrP的表达及PTHrP1-34中和抗体对疾病进展的影响。据报道，在类风湿关节炎中，虽然血清PTHrP水平在SCW诱导的关节炎期间没有变化，但PTHrP在关节炎滑膜中的表达显著增加。PTHrP中和抗体(与对照抗体相比)对SCW处理动物的关节肿胀没有影响。然而，PTHrP抗体显著抑制SCW诱导的关节破坏，通过其阻止血清吡啶酚(软骨和骨破坏的标志)的增加，关节软骨的侵蚀，股骨骨密度的降低，以及侵蚀骨中破骨细胞数量的增加来衡量。出乎意料的是，肝和脾中SCW沉积部位的肉芽肿形成也被PTHrP抗体抑制，这一效果与显著减少PTH/PTHrP受体阳性中性粒细胞的组织流入和SCW诱导的中性粒细胞减少有关。在体外，PTHrP1-34可刺激中性粒细胞趋化。这些发现表明，PTHrP与之前描述的在转移性骨疾病中的溶骨作用一致，也可以是炎症性骨病(如RA)中关节破坏的重要介质。此外，本研究揭示了迄今未知的PTHrP多肽对中性粒细胞功能的影响，这可能在炎性肉芽肿性疾病的发病机制中具有重要意义。
Objective. To determine whether parathyroid hormone-related protein (PTHrP), an interleukin-1beta-inducible, bone-resorbing peptide that is produced in increasing amounts by the synovium in rheumatoid arthritis (RA), may play a role in the pathophysiology of joint destruction in RA.Methods. PTHrP expression and the effect of PTHrP 1-34 neutralizing antibody on disease progression were tested in streptococcal cell wall (SCW-)induced arthritis, an animal model of RA.Results. As has been reported in RA, while serum levels of PTHrP did not change during SCW-induced arthritis, PTHrP expression dramatically increased in the arthritic synovium. Treatment with PTHrP neutralizing antibody (versus control antibody) did not affect joint swelling in SCW-treated animals. However, PTHrP antibody significantly inhibited SCW-induced joint destruction, as measured by its ability to block increases in serum pyridinoline (a marker of cartilage and bone destruction), erosion of articular cartilage, decreases in femoral bone mineral density, and increases in the numbers of osteoclasts in eroded bone. Unexpectedly, granuloma formation at sites of SCW deposition in the liver and spleen was also inhibited by PTHrP antibody, an effect associated with significant decreases in the tissue influx of PTH/PTHrP receptor-positive neutrophils and in SCW-induced neutrophilia. In vitro, neutrophil chemotaxis was stimulated by PTHrP 1-34.Conclusion. These findings suggest that PTHrP, consistent with its previously described osteolytic effects in metastatic bone disease, can also be an important mediator of joint destruction in inflammatory bone disorders, such as RA. Moreover, this study reveals heretofore unknown effects of PTHrP peptides on neutrophil function that could have important implications in the pathogenesis of inflammatory granulomatous disorders.