Groundbreaking research reveals the dual role of calcitonin gene-related peptide alpha in age-related osteoarthritis

Osteoarthritis (OA) emerges as the third fastest-growing disability-linked disease, affecting over 500 million individuals worldwide. The latest research published in Arthritis Research and Therapy unveils the dual role of calcitonin gene-related peptide alpha (αCGRP)in mouse models, shedding light on inflammation and bone protection in primary OA. 

Dr. Hildebrandt and team conducted the study involving female αCGRP−/− and wild-type (WT) mice, rigorously backcrossed over seven generations to maintain a pure C57BL/6 J genetic background. The mice were categorized into four groups based on age: Young mice aged 4-5 months (WTCTRL n = 10, αCGRP−/−CTRL n = 10) and aged mice, 16-18 months old (WTaged n = 10, αCGRP−/−aged n = 10). The study employed an age-dependent primary OA model previously documented in animals sharing the C57BL/6 J genetic lineage.  

The study findings revealed that the older WTaged mice exhibited significantly higher levels of αCGRP in their serum compared to the younger WTCTRL mice. The WTaged group showed significant cartilage damage due to OA, while the αCGRP-/-aged mice were largely shielded from these effects. This age-related OA correlated with an increased expression of inflammatory genes like Tnfa, Il1b, and Il6, as well as catabolic genes such as Mmp13, Adamts5, Ctsk, Tnfs11 (Rankl), and Cxcl12/Cxcr4 in the WTaged mice, not in the αCGRP-/-aged mice. The absence of αCGRP worsened subchondral bone sclerosis in the medial tibial plateau and increased bone loss in the epi- and metaphyseal trabecular tibial bone in age-related OA. 

CGRP, a nociceptive neuropeptide, contributes to pain perception and sensitization in OA. This 37-amino acid peptide belongs to the calcitonin (CT) peptide family and exists in two forms: αCGRP and βCGRP. αCGRP, encoded by the Calca gene, is expressed in various tissues including the central and peripheral nervous systems, while βCGRP, encoded by the Calcb gene, is primarily found in the intestine. In osteoarthritic joints, CGRP is present in intraarticular perivascular sensory nerve fibers and synovial fluid. It serves dual roles, acting as a nociceptive/sensory element and an efferent/effector, contributing to arthritic pain through CGRP-mediated neurogenic vasodilation and inflammation. The severity of OA is positively linked to the density of intraarticular CGRP-positive perivascular nerve fibers. 

The study exploring the dual role played by αCGRP in murine primary OA demonstrates its simultaneous pro-inflammatory and bone-protective functions. Despite previous attempts using anti-CGRP treatment that did not effectively alleviate OA pain in clinical settings, these findings underscore the pivotal pathophysiological role αCGRP plays in age-related OA. The study findings open new avenues for targeted therapeutic interventions that could potentially address the complex mechanisms involved in OA progression. 

Reference 

Hildebrandt A, Dietrich T, Weber J, Günderoth MM, Zhou S, Fleckenstein FN, et al. The dual pro-inflammatory and bone-protective role of calcitonin gene-related peptide alpha in age-related osteoarthritis. Arthritis Res Ther. 2023 Dec 15;25(1):244.  

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