Proinflammatory and bone protective role of calcitonin gene-related peptide alpha in collagen antibody-induced arthritis

Objectives. Calcitonin gene-related peptide alpha (alpha CGRP) represents an immunomodulatory neuropeptide implicated in pain perception. alpha CGRP 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 alpha CGRP in experimental RA regarding joint inflammation and bone remodelling. Methods. Collagen II-antibody-induced arthritis (CAIA) was induced in wild type (WT) and alpha CGRP-deficient (alpha CGRP(-/-)) 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 mu CT. Results. CAIA was accompanied by an overexpression of alpha CGRP in WT joints. alpha CGRP(-/-) mice displayed reduced arthritic inflammation and cartilage degradation. Congruently, the expression of TNF-alpha, IL-1 beta, CD80 and MMP13 was induced in WT, but not alpha CGRP(-/-) animals. WT mice displayed an increased bone turnover during the acute inflammatory phase, which was not the case in alpha CGRP(-/-) mice. Interestingly, WT mice displayed a full recovery from the inflammatory bone disease, whereas alpha CGRP(-/-) mice exhibited substantial bone loss over time. Conclusion. This study demonstrates a proinflammatory and bone protective role of alpha CGRP in CAIA. Our data indicate that alpha CGRP not only enhances joint inflammation, but also controls bone remodelling as part of arthritis resolution. As novel alpha CGRP inhibitors are currently introduced clinically for the treatment of migraine, their potential impact on RA progression warrants further clinical investigation.

Automated summary

The study revealed an inflammatory and bone-protective role of alpha CGRP in CAIA, showing that alpha CGRP enhances joint inflammation while controlling bone remodelling. This suggests that alpha CGRP inhibitors, currently used for migraine treatment, may have an impact on RA progression and require further clinical investigation.