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

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-b, inflammatory, and metabolic signaling. At 4-months, Crtap-/- mice showed increased aSMA, MMP2, and phospho-NFkB 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.

Biomechanical, Microstructural and Material Properties of Tendon and Bone in the Young Oim Mice Model of Osteogenesis Imperfecta

“…It is plausible that severe bone deformations observed in the area of the tendon insertion led to motor impairment. In a recent study also interested in the impact of the disease on the tendons [ 20 ], Crtap mice (a different model of OI) presented motor impairment and thinner tendons but an increase in collagen crosslinks and a dysregulation in inflammatory signalling. However, it is worth noting that, according to the newest OI classification, this model is in fact type VII and the effects at the tissue level are probably not exactly similar.…”

A Fibre Tracking Algorithm for Volumetric Microstructural Data - Application to Tendons

“…The fibrils in these mouse tendons were observed to be less regularly packed, with more space separating them than in the corresponding controls in the study [22] , and other groups have noted altered fibril morphology and diameter distributions in similar mod-els compared to wild-type tendons [23] . Mice with osteogenesis imperfecta type phenotypes often have tendons of a smaller size and show irregular fibril alignment [24] , so the accurate quantification of three-dimensional (3D) tendon microstructure is important in this field.…”

CD200 as a Potential New Player in Inflammation during Rotator Cuff Tendon Injury/Repair: An In Vitro Model

“…CD200 expression can be induced by pro-inflammatory cytokines, such as TNF-α and IFN-γ, in an NF-kB-, STAT1-, and IRF-1-dependent manner [ 14 , 15 ]. Interestingly, CD200 is expressed in several tissues/cells, including CD146+ stem cells originating from the Achilles and patellar tendons [ 16 ]. However, there are no data for CD200 expression and cytokine response in rotator cuff-derived tendon cells (RCTCs).…”

“…The study used human cells represented by thawed material that was cryopreserved during our previous studies [ 14 , 15 , 16 ]. In those papers (see Section 4 ), it was stated that all the procedures were approved by the Ethical Committee of Rome Tor Vergata University, that all patients gave written informed consent, and that all samples were anonymized before being processed.…”