Developmental, but not Homeostatic, Collagen V Expression Regulates Mature Murine Supraspinatus Tendon Structure, Function, and Gene Expression.

The development of tendon hierarchical structure is dependent on collagen I assembly into fibrils and higher-order assemblies, a process regulated by interactions involving collagen V, a quantitatively minor yet essential component of the tendon extracellular matrix. Collagen V critically regulates fibrillogenesis and is expressed throughout tendon development and maturation. Clinically, deficiency of collagen V manifests as classic Ehlers-Danlos syndrome (cEDS), a disorder characterized by hyperextensible skin, joint hypermobility and instability, and impaired wound healing. Recent studies in mouse supraspinatus tendons-which experience complex, region-dependent loading environments at insertion and midsubstance-demonstrate that developmental collagen V deficiency results in altered tendon structure and biomechanical function. However, differences in structure, mechanics, and gene expression resulting from reduced collagen V expression from embryonic development versus reduction during homeostasis have not been clearly delineated in mature tendons. To address this gap, this study elucidated the role of collagen V on region-specific tendon structural, functional, and compositional properties in mature, day 150 supraspinatus tendons. Tendon-targeted Col5a1 deficiency from embryonic development resulted in substantial structural, mechanical, and transcriptional alterations, including disrupted fibril organization, compromised mechanical properties, and altered gene expression profiles. Conversely, acute deficiency and knockdown of Col5a1 in mature tendons resulted in relatively minimal changes. Collectively, these findings identify a distinct and critical role for collagen V during tendon development, rather than homeostasis, in establishing region-specific multiscale structural, mechanical, and molecular properties essential for mature supraspinatus tendon function.