CGRP is essential for bone remodeling in the resolution phase of antibody-mediated arthritis

Objectives Rheumatoid arthritis (RA) is the most common autoimmune disease affecting 1 % of the world’s population, causing soft tissue inflammation, cartilage degradation and bone erosions predominantly in symmetrical joints. Reduced bone quality in RA patients leads to an increased risk of periprosthetic joint infections and periprosthetic fractures after total joint arthroplasty. To potentially improve bone quality in these patients, we investigated the role of calcitonin gene-related peptide (CGRP), a neuropeptide with a distinct role in nociception, inflammation and bone metabolism, in a murine autoantibody-mediated RA model. As we were previously able to show a pro-inflammatory role of CGRP in experimental RA, with the current study we further investigated the role CGRP in rheumatic bone remodeling.

Methods The effects of collagen antibody induced arthritis (CAIA) on the bone structure of CGRP-deficient mice (CGRP-/-) (n=11) and their wildtype (WT) littermates (n=12) were investigated at two time points that represent the acute (day 10) and resolution phase (day 48) of CAIA. Experimental animals received an arthritic collagen II antibody injection on day 0, while controls received phosphate-buffered saline (CGRP-/- n=8; WT n=8). Ex vivo micro-computed tomography (micro-CT) scans of the proximal tibiae were obtained on day 10 and day 48 to assess bone microarchitecture.

Results and Conclusion Acute arthritis led to a significant loss of bone surface in arthritic WT mice, while CGRP-/- animals showed no radiographic signs of alterations in bone microarchitecture compared to healthy controls at day 10. This was in line with the arthritic clinical scores, which were significantly more pronounced in arthritic WT animals compared to arthritic CGRP-/- animals. Arthritic CGRP-/- mice however showed significantly more TRAP expression at day 10 compared to their controls, demonstrating the presence of early bone resorption. After 48 days no significant differences between arthritic WT animals and their controls were observed, indicating physiological bone remodeling during the resolution phase of arthritis. In CGRP-/- animals however, the bone quality was significantly impaired after 48 days with reduced bone volume and decreased bone surface parameters compared to the control group. This finding underlines the relevance of intact CGRP signaling for bone remodeling and especially bone formation which takes place during the resolution phase.

Taken together, our study shows for the first time the bone-protective and osteoanabolic effects of CGRP in the resolution phase of acute antibody-mediated arthritis. As CGRP-targeting therapies are currently introduced clinically for the treatment of migraine disorders, the lasting effects of CGRP on bone metabolism should not be neglected. Further scientific engagement is required to unveil underlying molecular mechanisms of CGRP signaling on bone remodeling processes in chronic inflammatory bone diseases.

Stichwörter rheumatoid arthritis, CGRP, Calca, inflammation, autoimmune, bone remodeling

Publication History

Article published online:
15 October 2020