Collagen V is a quantitatively minor component of collagen fibrils, yet modulation of its expression hasdramatic phenotypic effects, indicating critical regulatory roles. Classic Ehlers?Danlos syndrome (EDS) is aheritable connective tissue disorder and is defined by collagen V mutations with haploinsufficiency for COL5A1present in ~67% of affected individuals. The classic form of EDS is characterized by hyperextensible skin, jointlaxity and instability, as well as abnormal wound healing. Additionally, collagen V has been linked to: Achillestendinopathy, ACL rupture, as well as injury and performance deficiencies due to altered matrix architectureand mechanical properties. Also, collagen V is significantly up-regulated after injury and altered expression isassociated with abnormal wound healing. Several recent studies have reported that the prevalence is heavilyskewed towards the female population, with ratios as high as 12:1 for female:male incidence. This difference ina genetic disease suggests gender related influence(s).Recent basic science studies suggest that differencesin hormone physiology between sexes may be a factor influencing tendon health. Specifically, females arereported to have increased joint laxity and a higher prevalence of tendon/ligament tears, typically attributed tohormone changes during the menstrual cycle as well as intrinsic differences in tendon biology betweengenders. Furthermore, recent evidence suggests that the injury response also may be altered in femaletendons, with decreased collagen synthesis, and altered gene expression in a number of importantinflammatory and repair factors with increased estrogen. Given the joint laxity and connective tissuehyperelasticity in classic EDS patients, gender-specific changes in hormone levels could further exacerbate thedetrimental changes present in pathological tendons, and significantly alter the injury response. The overallgoal of this competitive revision is to define the role of gender on tendon properties and in the tendon injuryresponse in normal and classic EDS tendons. Our general hypothesis is that: (a) tendon properties and (b) thetendon 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 femalecompared with male mice. Evaluation of the uninjured tendon structure and function will allow us to definebaseline differences in pathobiology associated with gender. This also will provide the foundation on which toevaluate changes during the injury response. We hypothesize that female classic EDS mice will have inferiorstructural, compositional, and mechanical properties compared to male classic EDS mice, but there will be nogender differences with wild type tendons.
Aim 2 : Elucidate the injury response in female classic EDS miceand compare this with the results from male mice. The haploinsufficient collagen V mouse model will allow thedefinition of gender-specific alterations in the injury response, and the influence of gender on collagen Vmediated mechanisms in the injury response.
Collagen V is a quantitatively minor component of collagen fibrils; yet modulation of its expression hasdramatic phenotypic effects; indicating critical regulatory roles. Classic Ehlers?Danlos syndrome (EDS) is aheritable connective tissue disorder and is defined by collagen V mutations with haploinsufficiency for COL5A1present in ~67% of affected individuals. Our general hypothesis is that: (a) tendon properties and (b) thetendon response to injury are modulated by gender-dependent collagen V mediated mechanism(s).
