Collagen V haploinsufficiency in female murine patellar tendons results in altered matrix engagement and cellular density, demonstrating decreased healing

Abstract

AbstractCollagen V (Col5) is a quantitatively minor component of collagen fibrils comprising tendon, however, plays a crucial role in regulation of development and dynamic healing processes. Clinically, patients with COL5a1 haploinsufficiency, known as classic Ehlers‐Danlos Syndrome (cEDS), present with hyperextensible skin, joint instability and laxity, with females more likely to be affected. Previous studies in Col5‐deficient mice indicated that reduced Col5a1 expression leads to a reduction in stiffness, fibril deposition, and altered fibril structure. Additionally, Col5‐deficient male tendons demonstrated altered healing compared to wild‐type tendons, however female mice have not yet been studied utilizing this model. Along with clinical differences between sexes in cEDS patient populations, differences in hormone physiology may be a factor influencing tendon health. Therefore, the objective of this study was to utilize a Col5a1+/− female mouse model, to determine the effect of Col5 on tendon cell morphology, cell density, tissue composition, and mechanical properties throughout healing. We hypothesized that reduction in Col5 expression would result in an abnormal wound matrix post‐injury, resulting in reduced mechanical properties compared to normal tendons. Following patellar tendon surgery, mice were euthanized at 1, 3, and 6‐week post‐injury. Col5‐deficient tendons demonstrated altered and decreased healing compared to WT tendons. The lack of resolution in cellularity by 6‐week post‐injury in Col5‐deficient tendons influenced the decreased mechanical properties. Stiffness did not increase post‐injury in Col5‐deficient mice, and collagen fiber realignment was delayed during mechanical loading. Therefore, increased Col5a1 expression post‐injury is necessary to re‐establish matrix engagement and cellularity throughout tendon healing.