Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Julius Wolff Institute, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Rheumatology (Oxford). 2021 Apr 6;60(4):1996-2009. doi: 10.1093/rheumatology/keaa711.
Calcitonin gene-related peptide alpha (αCGRP) represents an immunomodulatory neuropeptide implicated in pain perception. αCGRP also functions as a critical regulator of bone formation and is overexpressed in patients with rheumatoid arthritis (RA). In the present study, we investigated the role of αCGRP in experimental RA regarding joint inflammation and bone remodelling.
Collagen II-antibody-induced arthritis (CAIA) was induced in wild type (WT) and αCGRP-deficient (αCGRP-/-) mice. Animals were monitored over 10 and 48 days with daily assessments of the semiquantitative arthritis score and grip strength test. Joint inflammation, cartilage degradation and bone erosions were assessed by histology, gene expression analysis and µCT.
CAIA was accompanied by an overexpression of αCGRP in WT joints. αCGRP-/- mice displayed reduced arthritic inflammation and cartilage degradation. Congruently, the expression of TNF-α, IL-1β, CD80 and MMP13 was induced in WT, but not αCGRP-/- animals. WT mice displayed an increased bone turnover during the acute inflammatory phase, which was not the case in αCGRP-/- mice. Interestingly, WT mice displayed a full recovery from the inflammatory bone disease, whereas αCGRP-/- mice exhibited substantial bone loss over time.
This study demonstrates a proinflammatory and bone protective role of αCGRP in CAIA. Our data indicate that αCGRP not only enhances joint inflammation, but also controls bone remodelling as part of arthritis resolution. As novel αCGRP inhibitors are currently introduced clinically for the treatment of migraine, their potential impact on RA progression warrants further clinical investigation.
降钙素基因相关肽 α（αCGRP）是一种免疫调节神经肽，参与疼痛感知。αCGRP 还作为骨形成的关键调节剂发挥作用，在类风湿关节炎（RA）患者中过度表达。在本研究中，我们研究了 αCGRP 在实验性 RA 中对关节炎症和骨重塑的作用。
在野生型（WT）和 αCGRP 缺陷型（αCGRP-/-）小鼠中诱导胶原 II 抗体诱导性关节炎（CAIA）。通过半定量关节炎评分和握力测试，每天监测动物 10 天和 48 天。通过组织学、基因表达分析和 µCT 评估关节炎症、软骨降解和骨侵蚀。
CAIA 伴随着 WT 关节中 αCGRP 的过度表达。αCGRP-/-小鼠表现出关节炎炎症和软骨降解减少。相应地，WT 动物中诱导了 TNF-α、IL-1β、CD80 和 MMP13 的表达，但 αCGRP-/-动物中没有。WT 小鼠在急性炎症期表现出增加的骨转换，而 αCGRP-/-小鼠则没有。有趣的是，WT 小鼠从炎症性骨病中完全恢复，而 αCGRP-/-小鼠随着时间的推移表现出大量的骨质流失。
本研究表明 αCGRP 在 CAIA 中具有促炎和保护骨骼的作用。我们的数据表明，αCGRP 不仅增强关节炎症，而且控制骨重塑作为关节炎缓解的一部分。由于新型 αCGRP 抑制剂目前正在临床上用于治疗偏头痛，它们对 RA 进展的潜在影响需要进一步的临床研究。
