Beyond tendon interfaces – Functional divergence of the matricellular protein SPARC

Musculoskeletal tissue interfaces (TIs), including osteotendinous, myotendinous, and osteochondral junctions, are specialized regions that enable effective force transmission, mechanical stability, and long-term tissue integration. These interfaces are defined by gradients in cellular composition, extracellular matrix (ECM) organization, and mechanical properties, and their maintenance relies in part on tightly regulated cell-matrix interactions. Beyond structural ECM components, matricellular proteins such as Secreted Protein Acidic and Rich in Cysteine (SPARC), thrombospondins, osteopontin, periostin, and tenascins have emerged as critical modulators of interface biology by shaping ECM assembly, mechanotransduction, and adaptive cellular responses to load. SPARC has been shown to impact on collagen fibrillogenesis, ECM organization, and cell-matrix signaling across multiple musculoskeletal tissues. It is increasingly recognized as a regulator of load-bearing musculoskeletal tissue interfaces, where its dysregulation drives maladaptive remodeling marked by fibrosis, ectopic mineralization, and reduced regenerative capacity across pathologies such as tendinopathy, intervertebral disc disease, and osteoarthritis. This mini-review summarizes current knowledge on matricellular regulation at musculoskeletal tissue interfaces, with a focus on SPARC, integrating evidence from genetic models to investigate its role in interface homeostasis, mechanical adaptation, and pathological remodeling.