title: Tendon Extracellular Matrix Alterations in Ullrich Congenital Muscular Dystrophy.
abstract: Collagen VI (COLVI) is a non-fibrillar collagen expressed in skeletal muscle and most connective tissues. Mutations in COLVI genes cause two major clinical forms, Bethlem myopathy and Ullrich congenital muscular dystrophy (UCMD). In addition to congenital muscle weakness, patients affected by COLVI myopathies show axial and proximal joint contractures and distal joint hypermobility, which suggest the involvement of the tendon function. We examined a peroneal tendon biopsy and tenocyte culture of a 15-year-old patient affected by UCMD with compound heterozygous COL6A2 mutations. In patient's tendon biopsy, we found striking morphological alterations of tendon fibrils, consisting in irregular profiles and reduced mean diameter. The organization of the pericellular matrix of tenocytes, the primary site of collagen fibril assembly, was severely affected, as determined by immunoelectron microscopy, which showed an abnormal accumulation of COLVI and altered distribution of collagen I (COLI) and fibronectin (FBN). In patient's tenocyte culture, COLVI web formation and cell surface association were severely impaired; large aggregates of COLVI, which matched with COLI labeling, were frequently detected in the extracellular matrix. In addition, metalloproteinase MMP-2, an extracellular matrix-regulating enzyme, was increased in the conditioned medium of patient's tenocytes, as determined by gelatin zymography and western blot. Altogether, these data indicate that COLVI deficiency may influence the organization of UCMD tendon matrix, resulting in dysfunctional fibrillogenesis. The alterations of tendon matrix may contribute to the complex pathogenesis of COLVI related myopathies.
authors.affiliation: Department of Biomedical Sciences, University of PadovaPadova, Italy; National Research Council of Italy, Institute of Molecular GeneticsBologna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Sardone
authors.affiliation: Rizzoli Orthopaedic Institute, University of Bologna Bologna, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Traina
authors.affiliation: Rizzoli Orthopaedic Institute, University of Bologna Bologna, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Bondi
authors.affiliation: Muscle Clinic, Villa Erbosa Hospital, Gruppo San Donato Bologna, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Merlini
authors.affiliation: National Research Council of Italy, Institute of Molecular GeneticsBologna, Italy; SC Laboratory of Musculoskeletal Cell Biology, IOR-IRCCSBologna, Italy.
authors.forename: Spartaco
authors.initials: S
authors.lastname: Santi
authors.affiliation: National Research Council of Italy, Institute of Molecular GeneticsBologna, Italy; SC Laboratory of Musculoskeletal Cell Biology, IOR-IRCCSBologna, Italy.
authors.forename: Nadir Mario
authors.initials: NM
authors.lastname: Maraldi
authors.affiliation: Rizzoli Orthopaedic Institute, University of Bologna Bologna, Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Faldini
authors.affiliation: National Research Council of Italy, Institute of Molecular GeneticsBologna, Italy; SC Laboratory of Musculoskeletal Cell Biology, IOR-IRCCSBologna, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Sabatelli
keywords: Collagen VI; Ullrich congenital muscular dystrophy (UCMD); metalloproteinases; pericellular matrix; tendon