Bone phenotype in a mouse model of Classical Ehlers Danlos syndrome with Col5a1 haploinsufficiency.

Type V collagen is a key regulator in the formation of type I collagen fibrils in connective tissues including skin, tendons, and bones. Abnormalities in type V collagen cause classical Ehlers Danlos syndrome (EDS), a connective tissue disorder with primarily skin and joint phenotype. There are several clinical reports suggesting increased prevalence of vertebral fractures in adult patients with EDS, among them patients with classical EDS. Yet, the literature lacks data about bone health specifically in the classical EDS patient population. The Col5a1 haploinsufficient mouse model (Col5a1+/-) recapitulates the human disease phenotype with hyperextensible and fragile skin, delayed wound healing, and tendons with reduced tensile strength. The bone phenotype in this model is unknown. Here we present a comprehensive bone phenotyping of this model using 3-point bending, vertebral compression studies, micro computed tomography (microCT) analysis, Raman spectroscopy, and quantitative Backscattered Electron Imaging (qBEI) to test bone quantity, quality, composition, and mineralization density distribution. We found no difference in all parameters tested between Col5a1+/- and Col5a1+/+ mice 8 weeks and 6 months old in both sexes. Bulk RNA sequencing in tibiae from 8-week-old males identified only minimal changes in gene expression. Our results show that the Col5a1 haploinsufficient mouse model does not have a significant bone phenotype and suggest that individuals with heterozygote loss of function variants in COL5A1 may not have a higher risk for fractures due to primary bone abnormality.