Sdc4 deletion perturbs intervertebral disc matrix homeostasis and promotes early osteopenia in the aging mouse spine.

• Syndecan 4 null mice show vertebral osteopenia, reduced bone stiffness, and functionally altered bone biomechanics. • Osteopenic phenotype in Sdc4 null mice is driven by elevated osteoclast numbers. • Syndecan 4 fine-tunes collagen maturity and ECM composition in the intervertebral disc during early adult life. • Transcriptomic analysis shows dysregulation in heparan sulfate biosynthesis, UPR, and degradation along with decreased mitochondria metabolism. Syndecan 4 (SDC4), a cell surface heparan sulfate proteoglycan, is known to regulate matrix catabolism by nucleus pulposus cells in an inflammatory milieu. However, the role of SDC4 in the aging spine has never been explored. Here we analyzed the spinal phenotype of Sdc4 global knockout (KO) mice as a function of age. Micro-computed tomography showed that Sdc4 deletion severely reduced vertebral trabecular and cortical bone mass, and biomechanical properties of vertebrae were significantly altered in Sdc4 KO mice. These changes in vertebral bone were likely due to elevated osteoclastic activity. The histological assessment showed subtle phenotypic changes in the intervertebral disc. Imaging-Fourier transform-infrared analyses showed a reduced relative ratio of mature collagen crosslinks in young adult nucleus pulposus (NP) and annulus fibrosus (AF) of KO compared to wildtype discs. Additionally, relative chondroitin sulfate levels increased in the NP compartment of the KO mice. Transcriptomic analysis of NP tissue using CompBio, an AI-based tool showed biological themes associated with prominent dysregulation of heparan sulfate GAG degradation, mitochondria metabolism, autophagy, endoplasmic reticulum (ER)-associated misfolded protein processes and ER to Golgi protein processing. Overall, this study highlights the important role of SDC4 in fine-tuning vertebral bone homeostasis and extracellular matrix homeostasis in the mouse intervertebral disc. [ABSTRACT FROM AUTHOR]