Human hip osteoarthritis-associated Chadl variant induces intervertebral disc degeneration in mice

Abstract

Chondroadherin-like (CHADL), a small leucine-rich proteoglycan, plays a role in ECM assembly and chondrocyte differentiation. CHADL has been implicated in osteoarthritis (OA) due to the discovery of a rare frameshift variant (rs532464664) that confers one of the highest genetic risks for hip OA reported to date. In this study, we characterized the skeletal phenotypes of two mouse models of Chadl loss-of-function, a global null and an 8bp insertion that mimics the human frameshift variant. Surprisingly, while there was a slight increase in knee OA at 12 months, there were no genotype-based differences in knee or hip OA in aged mice. Interestingly, histological assessment revealed phenotypic changes in the intervertebral discs of mutant mice, along with increased disc height index, suggesting altered motion-segment biomechanics. Polarized imaging showed dysregulated collagen turnover in the annulus fibrosus (AF), evidenced by changes in the proportions of thin and intermediate fibers. There was decreased abundance of the nucleus pulposus (NP) marker CA3 and decreased staining for ECM proteins in the AF of mutants. CHADL loss affected vertebral trabecular architecture, cortical thickness, and mineral density. This study highlights an unrecognized role of CHADL in fine-tuning ECM homeostasis and health of the intervertebral disc and vertebral bone.