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Mechanical loading through exercise can either exacerbate or alleviate OA symptoms depending on intensity. Substance P (SP), a neuropeptide involved in inflammation and mechanotransduction, has been implicated in cartilage and bone remodeling. This study aimed to investigate how SP deficiency plus exercise intensity interact to influence disease progression in a surgical murine OA model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>OA was induced in male wild-type (WT) and SP knockout (Tac1-\/-) mice via destabilization of the medial meniscus (DMM). Mice were then exposed to moderate or intense treadmill exercise for up to eight weeks. Cartilage degeneration was assessed histologically using OARSI scoring. Cartilage stiffness was evaluated via atomic force microscopy (AFM), and subchondral and metaphyseal bone morphology was analyzed by high-resolution nanoCT. Serum cytokine levels were measured with multiplex ELISA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>DMM surgery induced OA-like cartilage damage in most groups, and moderate exercise failed to prevent degeneration. However, SP-deficient mice subjected to intense exercise showed preserved cartilage matrix stiffness and morphology comparable to Sham controls. In contrast, SP deficiency as well as intense exercise promoted meniscal ossification and subchondral bone sclerosis, with increased bone volume fraction and trabecular thickness. These changes were consistent with prior findings in SP-deficient mice without exercise. Serum analysis revealed elevated levels of proinflammatory cytokines (e.g., CXCL10, VEGF-A, CCL2, CCL4) in SP-deficient mice after Sham surgery, although these did not correspond to the cartilage degradation timeline.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>SP plays a dual role in OA pathogenesis: its absence may protect cartilage from mechanical stress\u2013induced stiffening but also promotes ectopic meniscal ossification and subchondral bone alterations. Additionally, SP appears to modulate systemic inflammatory responses independently of joint degeneration. These findings position SP as a key regulator of neuroimmune and mechanobiological processes in OA and highlight its potential as a therapeutic target for load-induced joint pathology.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13075-025-03693-7","type":"journal-article","created":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T10:55:08Z","timestamp":1764845708000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Exercise-Dependent effects of substance P deficiency on joint degeneration and inflammation in a surgical mouse model of osteoarthritis"],"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":[[2025,12,4]]},"reference":[{"key":"3693_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2020.100587","volume":"29","author":"A Cui","year":"2020","unstructured":"Cui A, Li H, Wang D, Zhong J, Chen Y, Lu H. 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