EXPLORING THE INVOLVEMENT OF COLVI-NG2 AXIS IN THE GENERATION OF CONTRACTURES AFFECTING UCMD PATIENTS

 

Mutations of collagen VI (Col VI) cause Ullrich Congenital Muscular Dystrophy (UCMD), a severe disease leading patients also to suffer from invalidating contractures. While identifying the molecular cause of contractures will help in planning therapeutic strategies, increasing evidences suggest tendon and muscle fascia dysfunction as a major cause.

On the basis of our previous findings (altered collagen fibrillogenesis in an UCMD tendon biopsy and in animal models of collagen VI disorders), we hypothesize that altered collagen VI binding with the cell membrane may affect proper collagen I fibrils formation in tendons and muscle fascia cells because: 

– NG2 proteoglycan mediates binding of collagen VI with the cell membrane

– inhibiting collagen VI-NG2 binding impairs cell migration and response to mechanical stress

– mutations in COL6A2 gene causing UCMD affect NG2 expression

– increased degradation of NG2 by MMP2 and its deregulation by TGFbeta1 disrupt the integrity of collagen VI-NG2 axis in UCMD.

In this study we plan to extend our preliminary observations to a significant number of cultured tendon and muscle fascia cells provided by clinical units during orthopedic surgical corrective interventions of UCMD patients. We will:

– assess RNA profiling to evaluate the transcription level of CSPG4  (encoding NG2 proteoglycan) and of genes involved in its deregulation,  MMP2 (coding for the enzyme matrix metalloproteinase-2) and TGFB1(coding for the cytokine transforming growth factor beta1)

– assess the effect of MMP2 and TGFbeta1 on normal tendon and fascia cells and 3D models to explore the role of these molecules in determining UCMD cell phenotype

–  treat in vitro UCMD cells and 3D models with inhibitors of MMP2 activity and TGFbeta1 signaling in order to pave the way to future therapeutic applications