Tendon and motor phenotypes in the Crtap-/- mouse model of recessive osteogenesis imperfecta
Matthew W. Grol, Nele A Haelterman, Joohyun Lim, Elda Munivez, Marilyn Archer, David M. Hudson, Sara F. Tufa, Douglas R. Keene, Kevin Lei, Dongsu Park, Cole D Kuzawa, Catherine G. Ambrose, David R. Eyre, Brendan Lee
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.