SDC4 deletion perturbs intervertebral disc matrix homeostasis and promotes early osteopenia in the aging spine

Abstract

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 due to elevated osteoclastic activity in KO mice. The histological assessment also showed subtle phenotypic changes in the intervertebral discs. Imaging-Fourier transform-infrared (FTIR) analyses showed a reduced relative ratio of mature collagen crosslink in young adult NP and AF compartments of KO compared to wildtype (WT) mice. Additionally, relative chondroitin sulfated glycosaminoglycan (GAG) 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, and endoplasmic reticulum 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 intervertebral disc.

Proteoglycan Dysfunction: A Common Link Between Intervertebral Disc Degeneration and Skeletal Dysplasia

“…Importantly, the transcriptomic analysis suggested that Sdc4 deletion downregulates genes associated with mitochondrial metabolism, autophagy, ER to Golgi protein processing, and HS biosynthesis and GAG degradation. These findings indicate that deletion of Sdc4 reduces matrix turnover which is speculated to be responsible for CS accumulation and GAG degradation in NP tissue [ 107 ]. Other investigators using Has2 - and Sulf1 -knockout mice have demonstrated the important of GAG function in PGs.…”

“…These findings indicate that deletion of Sdc4 reduces matrix turnover which is speculated to be responsible for CS accumulation and GAG degradation in NP tissue. 107 Other investigators using Has2-and Sulf1-knockout mice have demonstrated the important of GAG function in PGs. Changes in hyaluronan synthesis and sulfation of GAG profiles can alter the structure and function of PGs.…”