The neuropeptide aCGRP impairs the chondrocyte response to mechanical load

ObjectiveNovel targets for osteoarthritis therapy are urgently needed, and sensory nerve fibres and their neuropeptides are increasingly recognised for their contribution to structural aspects of joint pathology. The nociceptive sensory neuropeptide alpha calcitonin gene-related peptide (CGRP) was previously detected in synovial fluid and serum of osteoarthritis patients and was also described as trophic factor for chondrocytes, affecting ECM organisation and biomechanical properties. Here, we investigated the potential of CGRP to alter the chondrocyte mechanoresponse, and thus to affect the resilience of cartilage towards mechanical loading. MethodsTissue-engineered neocartilage based on human articular chondrocytes was treated with 1{micro}M CGRP for 24 hours and subjected to an anabolic loading protocol (intermittent dynamic compression, 1Hz, 25%) for the last 3 hours before analysing its molecular mechano-response. ResultsMechanotransduction was largely unaltered by CGRP as demonstrated by ERK activation and stimulation of mechano-regulated gene expression, yet load-stimulated glycosaminoglycan synthesis was disturbed by CGRP. Presence of CGRP did not affect stimulation of WNT5A expression by loading, but decreased DKK3 expression under loading. Importantly, WNT inhibition prevented the negative effect of CGRP on load-stimulated glycosaminoglycan synthesis. ConclusionIdentifying WNT5A as a novel mechano-response gene, we reveal that CGRP can block the load-stimulated proteoglycan production of human chondrocytes in the presence of WNT pathway activity. Thus, our data propose a novel, negative role for the pain-mediator CGRP in the cartilage loading response, compromising its resilience to loading. Overall, our study implicates CGRP as a potential target for osteoarthritis treatment, but also in patient stratification.