Collagen V haploinsufficiency in a murine model of classic Ehlers–Danlos syndrome is associated with deficient structural and mechanical healing in tendons

Abstract

Classic Ehlers-Danlos syndrome (EDS) patients suffer from connective tissue hyperelasticity, joint instability, skin hyperextensibility, tissue fragility, and poor wound healing due to heterozygous mutations in COL5a1 or COL5a2 genes. This study investigated the roles of collagen V in establishing structure and function in uninjured patellar tendons as well as in the injury response using a Col5a1+/− mouse, a model for classic EDS. These analyses were done comparing tendons from a classic EDS model (Col5a1+/−) with wild type controls. Tendons were subjected to mechanical testing, histological and fibril analysis before injury as well as 3 weeks and 6 weeks after injury. We found that Col5a1+/− tendons demonstrated diminished recovery of mechanical competency after injury as compared to normal wild type tendons, which recovered their pre-injury values by 6 weeks post injury. Additionally, the Col5a1+/−tendons demonstrated altered fibril morphology and diameter distributions compared to the wild type tendons. This study indicates that collagen V plays an important role in regulating collagen fibrillogenesis and the associated recovery of mechanical integrity in tendons after injury. In addition, the dysregulation with decreased collagen V expression in EDS is associated with a diminished injury response. The results presented herein have the potential to direct future targeted therapeutics for classic EDS patients.

Change in Collagen Fibril Diameter Distribution of Bovine Anterior Cruciate Ligament upon Injury Can Be Mimicked in a Nanostructured Scaffold

“…One interesting characteristic of tendon/ligament tissues is the reduction in mean collagen fibril diameter and a shift in fibril diameter distribution from bimodal to unimodal distribution. Such a structural variation was previously studied using different species for different tendon/ligament tissues, including human ACL [ 25 ], rabbit MCL [ 27 ], and mouse/rat PT [ 29 , 30 ]. Collagen fibril diameter distribution of rabbit MCL with two peaks at ~40 and ~190 nm changed to exhibit a single peak at ~50 nm.…”

Post-Adipose-Derived Stem Cells (ADSC) Stimulated by Collagen Type V (Col V) Mitigate the Progression of Osteoarthritic Rabbit Articular Cartilage

“…Col V specifically decreases endothelial cell proliferation promoting cell detachment by the disassembly of F-actin filaments, and cells started to proliferate when recultured on Col I ( Mak et al, 2016 ). Moreover, heterozygous mutation in Col Va2 gene could lead to connective tissue hyperelasticity and joint instability ( Johnston et al, 2017 ). In the current study, we verified that ADSCs stimulated by Col V increased Col II synthesis, the main collagenous protein of the hyaline cartilage matrix, and decreased apoptotic chondrocytes.…”

Compound phenotype of osteogenesis imperfecta and Ehlers–Danlos syndrome caused by combined mutations inCOL1A1andCOL5A1

“…Type V collagen intercalates into the core of type I collagen fibrils, where it is involved in the organization and regulation of type I collagen fibril diameter [21]. In col5a1 +/− mice, tendons have larger diameter fibrils, resulting in an irregular shape [22]. Irregularly shaped fibrils generate a diminished dynamic mechanical response of col5a1 +/− tendons [22], and COL5A1 mutations give rise to structural tendon pathology and low tendon stiffness responsible for joint hypermobility [23].…”

“…In col5a1 +/− mice, tendons have larger diameter fibrils, resulting in an irregular shape [22]. Irregularly shaped fibrils generate a diminished dynamic mechanical response of col5a1 +/− tendons [22], and COL5A1 mutations give rise to structural tendon pathology and low tendon stiffness responsible for joint hypermobility [23]. The COL5A1 mutation (c.5335A>G) results in a change from asparagine to aspartic acid.…”