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.

Public Health Relevance

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).

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
3R01AR065995-03S1
Application #
9308530
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Tyree, Bernadette
Project Start
2014-07-01
Project End
2019-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
3
Fiscal Year
2016
Total Cost
$100,000
Indirect Cost
$33,701
Name
University of Pennsylvania
Department
Orthopedics
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Johnston, Jessica M; Connizzo, Brianne K; Shetye, Snehal S et al. (2017) Collagen V haploinsufficiency in a murine model of classic Ehlers-Danlos syndrome is associated with deficient structural and mechanical healing in tendons. J Orthop Res 35:2707-2715
Connizzo, Brianne K; Adams, Sheila M; Adams, Thomas H et al. (2016) Collagen V expression is crucial in regional development of the supraspinatus tendon. J Orthop Res 34:2154-2161
Connizzo, Brianne K; Adams, Sheila M; Adams, Thomas H et al. (2016) Multiscale regression modeling in mouse supraspinatus tendons reveals that dynamic processes act as mediators in structure-function relationships. J Biomech 49:1649-1657
Screen, Hazel R C; Berk, David E; Kadler, Karl E et al. (2015) Tendon functional extracellular matrix. J Orthop Res 33:793-9
Sun, Mei; Connizzo, Brianne K; Adams, Sheila M et al. (2015) Targeted deletion of collagen V in tendons and ligaments results in a classic Ehlers-Danlos syndrome joint phenotype. Am J Pathol 185:1436-47
Connizzo, Brianne K; Freedman, Benjamin R; Fried, Joanna H et al. (2015) Regulatory role of collagen V in establishing mechanical properties of tendons and ligaments is tissue dependent. J Orthop Res 33:882-8