Tendon and motor phenotypes in the Crtap-/- mouse model of recessive osteogenesis imperfecta.

Brendan H Lee,Matthew William Grol,Catherine G Ambrose,Dongsu Park,David M Hudson,Cole D Kuzawa,Joohyun Lim,David R Eyre,Sara F Tufa,Elda M Munivez,Douglas R Keene,Kevin Lei,Marilyn Archer,Nele A Haelterman

doi:10.7554/elife.63488

Abstract

Osteogenesis imperfecta (OI) is characterized by short stature, skeletal deformities, low bone mass, and motor deficits. A subset of OI patients also present with joint hypermobility; however, the role of tendon dysfunction in OI pathogenesis is largely unknown. Using the Crtap-/- mouse model of severe, recessive OI, we found that mutant Achilles and patellar tendons were thinner and weaker with increased collagen cross-links and reduced collagen fibril size at 1- and 4-months compared to wildtype. Patellar tendons from Crtap-/- mice also had altered numbers of CD146+CD200+ and CD146-CD200+ progenitor-like cells at skeletal maturity. RNA-seq analysis of Achilles and patellar tendons from 1-month Crtap-/- mice revealed dysregulation in matrix and tendon marker gene expression concomitant with predicted alterations in TGF-β, inflammatory, and metabolic signaling. At 4-months, Crtap-/- mice showed increased αSMA, MMP2, and phospho-NFκB staining in the patellar tendon consistent with excess matrix remodeling and tissue inflammation. Finally, a series of behavioral tests showed severe motor impairments and reduced grip strength in 4-month Crtap-/- mice - a phenotype that correlates with the tendon pathology.

Highlights

Osteogenesis imperfecta (OI) is a heterogeneous group of disorders characterized by variable short stature, skeletal deformities, low bone mass, and increased bone fragility
By 4 months of age, Crtap-/- Achilles and patellar tendons remained thinner and hypercellular compared to wildtype and heterozygous mice (Figure 1G-L,N). Interestingly, ectopic chondrogenesis was present towards either end of the patellar tendon in some 4-month-old Crtap-/- mice (Figure 1L) – a phenomenon that can occur in tendinopathy[28]
To examine how collagen fibril alignment is affected by the loss of cartilage-associated protein (CRTAP), we examined longitudinal sections of flexor digitorum longus (FDL), Achilles, and patellar tendons from 4-month wildtype 166 and Crtap-/- mice using transmission electron microscopy (TEM) (Figure 4M-R)

Summary

Introduction

OI is a heterogeneous group of disorders characterized by variable short stature, skeletal deformities, low bone mass, and increased bone fragility. By 4 months of age, Crtap-/- Achilles and patellar tendons remained 109 thinner and hypercellular compared to wildtype and heterozygous mice (Figure 1G-L,N). Consistent with our histological data, phase-contrast μCT analysis demonstrated that patellar tendon volume was reduced in Crtap-/-, but not in heterozygous mice, compared to wildtype controls (Figure 1O-Q).

Results

Conclusion