The dual pro-inflammatory and bone-protective role of calcitonin gene-related peptide alpha in age-related osteoarthritis

Abstract

Background The vasoactive neuropeptide calcitonin gene-related peptide alpha (alpha CGRP) enhances nociception in primary knee osteoarthritis (OA) and has been shown to disrupt cartilage and joint integrity in experimental rheumatoid arthritis (RA). Little is known about how alpha CGRP may alter articular structures in primary OA. We investigated whether alpha CGRP modulates local inflammation and concomitant cartilage and bone changes in a murine model of age-dependent OA.MethodsSixteen- to 18-month-old alpha CGRP-deficient mice (alpha CGRP-/-aged) were compared to, first, age-matched wild type (WTaged) and, second, young 4- to 5-month-old non-OA alpha CGRP-deficient (alpha CGRP-/-CTRL) and non-OA WT animals (WTCTRL). alpha CGRP levels were measured in serum. Knee and hip joint inflammation, cartilage degradation, and bone alterations were assessed by histology (OARSI histopathological grading score), gene expression analysis, and mu-computed tomography.ResultsWTaged mice exhibited elevated alpha CGRP serum levels compared to young WTCTRL animals. Marked signs of OA-induced cartilage destruction were seen in WTaged animals, while alpha CGRP-/-aged mice were mostly protected from this effect. Age-dependent OA was accompanied by an increased gene expression of pro-inflammatory Tnfa, Il1b, and Il6 and catabolic Mmp13, Adamts5, Ctsk, Tnfs11 (Rankl), and Cxcl12/Cxcr4 in WTaged but not in alpha CGRP-/-aged mice. alpha CGRP-deficiency however further aggravated subchondral bone sclerosis of the medial tibial plateau and accelerated bone loss in the epi- and metaphyseal trabecular tibial bone in age-dependent OA.ConclusionsSimilar to its function in experimental RA, alpha CGRP exerts a dual pro-inflammatory and bone-protective function in murine primary OA. Although anti-CGRP treatment was previously not successful in reducing pain in OA clinically, these data underline a crucial pathophysiological role of alpha CGRP in age-related OA.