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The base of the mouse caudal spine region Ca3-6 that naturally experiences increased flexion, showed adaptive tissue remodeling, reminiscent of disc degeneration in young adult mice. Given the role of Syndecan 4 (SDC4), a cell surface heparan sulfate proteoglycan in disc matrix turnover and mechanosensing, we investigated if deletion could mitigate this loading-dependent phenotype. Notably, at spinal levels Ca3-6,\n                    <jats:italic>Sdc4-<\/jats:italic>\n                    knockout (KO) mice did not exhibit increased collagen fibril and fibronectin deposition in the nucleus pulposus (NP) compartment or showed the alterations in collagen crosslinks observed in wild-type mice. Similarly, unlike wild-type mice, NP cells in\n                    <jats:italic>Sdc4<\/jats:italic>\n                    -KO mice retained transgelin (TAGLN) expression and showed absence of collagen type X (COL10) deposition, pointing to the preservation of their notochordal characteristics. Proteomic analysis revealed that NP tissues responded to the altered loading by increasing the abundance of proteins associated with extracellular matrix remodeling, chondrocyte development, and contractility. Similarly, downregulated proteins suggested decreased vesicle transport, autophagy-related pathway, and RNA quality control regulation. Notably, NP proteome from\n                    <jats:italic>Sdc4-<\/jats:italic>\n                    KO suggested that increased dynamin-mediated endocytosis, autophagy-related pathway, and RNA and DNA quality control may underscore the protection from adaptive tissue remodeling caused by this naturally observed altered loading. Our study highlights the important role of SDC4 in fine-tuning cellular homeostasis and extracellular matrix production in disc environment subjected to altered loading.\n                  <\/jats:p>","DOI":"10.1038\/s41419-025-08002-3","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T06:20:54Z","timestamp":1759731654000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["SDC4 drives fibrotic remodeling of the intervertebral disc under altered spinal loading"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9164-1529","authenticated-orcid":false,"given":"Kimheak","family":"Sao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3913-0649","authenticated-orcid":false,"given":"Makarand V.","family":"Risbud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,6]]},"reference":[{"key":"8002_CR1","doi-asserted-by":"publisher","first-page":"e316","DOI":"10.1016\/S2665-9913(23)00098-X","volume":"5","author":"Collaborators GBDLBP.","year":"2023","unstructured":"Collaborators GBDLBP. 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