Small Proteoglycans, Big Impact: Decorin, Biglycan, and Asporin in Musculoskeletal Tissue Health and Disease

The extracellular matrix (ECM) is a dynamic and information‐rich network that integrates structural support with biochemical and mechanical signaling. Among its key regulatory components are the Small Leucine‐Rich Proteoglycans (SLRPs), a family of matrix molecules that coordinate extracellular architecture with cell signaling. Within this family, the Class I SLRPs decorin (DCN), biglycan (BGN), and asporin (ASPN) play central roles in the maintenance of musculoskeletal tissues' homeostasis. This review provides a comprehensive overview of the structural features, molecular interactions, and biological functions of DCN, BGN, and ASPN across musculoskeletal tissues in health and disease. We discuss how these SLRPs regulate collagen fibrillogenesis, extracellular matrix (ECM) assembly, and mechanotransduction while simultaneously modulating growth factor signaling pathways, particularly those involving Transforming Growth Factor‐ β (TGF‐β) and related regulators of tissue remodeling. Evidence from bone, cartilage, tendon, intervertebral disc, and skeletal muscle demonstrates their context‐dependent involvement in matrix organization and cellular responsiveness to mechanical cues. Alterations in Class I SLRPs contribute pivotally to both common and rare musculoskeletal disorders. In addition to their involvement in prevalent conditions such as osteoarthritis, osteoporosis, and tendon degeneration, dysregulation of SLRP‐mediated ECM signaling is also implicated in rare connective tissue disorders, including osteogenesis imperfecta, gerodermia osteodysplastica, musculo‐contractural Ehlers–Danlos syndrome, and biglycan‐related spondyloepimetaphyseal dysplasia. By integrating structural, mechanobiological, and signaling perspectives, this review highlights Class I SLRPs as central regulators of ECM organization and signaling in musculoskeletal tissues, providing a framework to understand their roles in musculoskeletal disorders.