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Mechanical stress, such as exercise, can influence OA progression, acting as either a therapeutic intervention or a risk factor depending on intensity. The sensory neuropeptide \u03b1CGRP plays a role in modulating cartilage, bone, and inflammatory responses, making it a potential mediator of exercise effects on OA. This study investigated the impact of \u03b1CGRP deficiency and exercise intensity on OA progression in a post-traumatic murine model. <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>OA was induced in male \u03b1CGRP knockout (KO) and wild type (C57Bl\/6J) mice via destabilization of the medial meniscus (DMM). Mice underwent moderate or intense treadmill exercise for up to 6 weeks (8 weeks post-surgery). Histological analyses were performed to assess cartilage degradation. Subchondral and metaphyseal bone morphology as well as cartilage stiffness were evaluated by nanoCT and atomic force microscopy (AFM), respectively. Serum inflammatory markers were analyzed using multiplex immunoassays.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Serum levels of proinflammatory markers were elevated in \u03b1CGRP-deficient mice, particularly after intense exercise, independent of OA progression. DMM surgery induced significant cartilage degradation. Gross cartilage morphology was not influenced by exercise intensity or \u03b1CGRP deficiency, but \u03b1CGRP deficiency prevented articular cartilage extracellular matrix stiffening after DMM and intense exercise. Subchondral bone sclerosis was induced by \u03b1CGRP deficiency and DMM but mitigated by intense exercise. In metaphyseal bone, intense exercise induced trabecular loss in \u03b1CGRP-deficient mice.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>This study highlights \u03b1CGRP as an intrinsic regulator of joint and bone responses to mechanical loading during OA. While cartilage degradation after DMM and treadmill exercise was unaffected by lack of \u03b1CGRP, its deficiency altered ECM stiffness, bone remodeling, and inflammatory responses. These findings position \u03b1CGRP as a critical regulator of joint homeostasis, particularly for bone health during running exercise and OA progression.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s13075-025-03589-6","type":"journal-article","created":{"date-parts":[[2025,6,21]],"date-time":"2025-06-21T09:05:40Z","timestamp":1750496740000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Decoding the impact of exercise and \u03b1CGRP signaling on murine post-traumatic osteoarthritis progression"],"prefix":"10.1186","volume":"27","author":[{"given":"Patrick","family":"Pann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Kalke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verena","family":"Maier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Sch\u00e4fer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hauke","family":"Clausen-Schaumann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arndt F.","family":"Schilling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Gr\u00e4ssel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,21]]},"reference":[{"key":"3589_CR1","doi-asserted-by":"crossref","unstructured":"Cui A, Li H, Wang D, Zhong J, Chen Y, Lu H. 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