SDC4 drives fibrotic remodeling of the intervertebral disc under altered spinal loading

Alterations in physiological loading of the spine are deleterious to intervertebral disc health. The caudal spine region Ca3-6 that experiences increased flexion, showed disc degeneration in young adult mice. Given the role of Syndecan 4 (SDC4), a cell surface heparan sulfate proteoglycan in disc matrix catabolism and mechanosensing, we investigated if deletion could mitigate this loading-dependent phenotype. Notably, at spinal levels Ca3-6, Sdc4- KO mice did not exhibit increased collagen fibril and fibronectin deposition in the NP compartment or showed the alterations in collagen crosslinks observed in wild-type mice. Similarly, unlike wild-type mice, NP cells in Sdc4 -KO mice retained transgelin (TGLN) expression and showed absence of COL X deposition, pointing to the preservation of their notochordal characteristics. Proteomic analysis revealed that NP tissues responded to the abnormal 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 Sdc4 KO suggested that increased dynamin-mediated endocytosis, autophagy-related pathway, and RNA and DNA quality control may underscore the protection from increased flexion-induced degeneration. Our study highlights the important role of SDC4 in fine-tuning cellular homeostasis and extracellular matrix production in disc environment subjected to altered loading.