Collagen V is a quantitatively minor component of collagen fibrils, yet modulation of its expression has dramatic phenotypic effects, indicating critical regulatory roles. Classic Ehlers?Danlos syndrome (EDS) is a heritable connective tissue disorder and is defined by collagen V mutations with haploinsufficiency for COL5A1 present in ~67% of affected individuals. The classic form of EDS is characterized by hyperextensible skin, joint laxity and instability, as well as abnormal wound healing. Additionally, collagen V has been linked to: Achilles tendinopathy, ACL rupture, as well as injury and performance deficiencies due to altered matrix architecture and mechanical properties. Also, collagen V is significantly up-regulated after injury and altered expression is associated with abnormal wound healing. Several recent studies have reported that the prevalence is heavily skewed towards the female population, with ratios as high as 12:1 for female:male incidence. This difference in a genetic disease suggests gender related influence(s).Recent basic science studies suggest that differences in hormone physiology between sexes may be a factor influencing tendon health. Specifically, females are reported to have increased joint laxity and a higher prevalence of tendon/ligament tears, typically attributed to hormone changes during the menstrual cycle as well as intrinsic differences in tendon biology between genders. Furthermore, recent evidence suggests that the injury response also may be altered in female tendons, with decreased collagen synthesis, and altered gene expression in a number of important inflammatory and repair factors with increased estrogen. Given the joint laxity and connective tissue hyperelasticity in classic EDS patients, gender-specific changes in hormone levels could further exacerbate the detrimental changes present in pathological tendons, and significantly alter the injury response. The overall goal of this competitive revision is to define the role of gender on tendon properties and in the tendon injury response in normal and classic EDS tendons. Our general hypothesis is that: (a) tendon properties and (b) the tendon response to injury are modulated by gender-dependent collagen V mediated mechanism(s). The aims are to: Aim 1: Define the structural, compositional, and mechanical properties of classic EDS tendons in female compared with male mice. Evaluation of the uninjured tendon structure and function will allow us to define baseline differences in pathobiology associated with gender. This also will provide the foundation on which to evaluate changes during the injury response. We hypothesize that female classic EDS mice will have inferior structural, compositional, and mechanical properties compared to male classic EDS mice, but there will be no gender differences with wild type tendons. Aim 2: Elucidate the injury response in female classic EDS mice and compare this with the results from male mice. The haploinsufficient collagen V mouse model will allow the definition of gender-specific alterations in the injury response, and the influence of gender on collagen V mediated mechanisms in the injury response.