RESUMO
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-ß, 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.
Assuntos
Tendão do Calcâneo/patologia , Proteínas da Matriz Extracelular/deficiência , Atividade Motora , Osteogênese Imperfeita/patologia , Osteogênese Imperfeita/fisiopatologia , Ligamento Patelar/patologia , Tendão do Calcâneo/metabolismo , Actinas/metabolismo , Fatores Etários , Animais , Modelos Animais de Doenças , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Proteínas da Matriz Extracelular/genética , Colágenos Fibrilares/genética , Colágenos Fibrilares/metabolismo , Genes Recessivos , Predisposição Genética para Doença , Força da Mão , Metaloproteinase 2 da Matriz/metabolismo , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Chaperonas Moleculares/genética , NF-kappa B/metabolismo , Osteogênese Imperfeita/genética , Osteogênese Imperfeita/metabolismo , Ligamento Patelar/metabolismo , Fenótipo , Fosforilação , Resistência Física , Células-Tronco/metabolismo , Células-Tronco/patologiaRESUMO
Although an understanding of bone material properties is crucial for interpreting and predicting fracture patterns due to injury or defining the effects of disease on bone strength, information about infant bone properties is scant in the literature. In this study we present the mechanical testing results from 47 tibia and 52 rib specimens taken from 53 infant decedents in order to further our understanding of infant bone strength. Bone specimens were imaged using microCT and tested in three-point bending until failure. Extrinsic and intrinsic properties demonstrated an increase in strength and stiffness over the first year of life, while ductility measures remained largely unchanged. Donor race had no effect on the material properties, but tibia bone specimens showed significant sex differences, with the elastic modulus from females being larger than males. When compared to properties from adolescent and adult donors, infant bone is less strong, less stiff, and more ductile.
