Proteoglycan Dynamics and Bone Quality: Molecular Regulation to Age-Related Fragility.

Clinically, bone mineral density (BMD) accounts for only approximately 50% of the observed variance in bone fragility fractures. This review examines the dynamic and mechanistic role of the non-collagenous organic matrix, specifically proteoglycans (PGs) and glycosaminoglycans (GAGs), in maintaining bone toughness and bone quality. During aging, bulk cortical GAG levels decrease by up to ~17% and are highly associated with reduced bone tissue toughness. We analyze how this age-related loss may arise from uncoupled bone remodeling and tissue aging, including the accumulation of older, interstitial tissue and dysregulated osteocyte-mediated matrix maintenance. We then discuss the functional importance of PG/GAG composition, maturation, and catabolism and how perturbations in these processes can promote pro-inflammatory signaling that accelerates matrix degradation and contributes to systemic aging. Lastly, we discuss potential interventions to preserve or restore GAGs/PGs in bone and improve overall bone quality.