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

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-beta, inflammatory, and metabolic signaling. At 4-months, Crtap(-/-) mice showed increased alpha SMA, MMP2, and phospho-NF kappa B 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.