title: A mouse model offers novel insights into the myopathy and tendinopathy often associated with pseudoachondroplasia and multiple epiphyseal dysplasia.
abstract: Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are relatively common skeletal dysplasias belonging to the same bone dysplasia family. PSACH is characterized by generalized epi-metaphyseal dysplasia, short-limbed dwarfism, joint laxity and early onset osteoarthritis. MED is a milder disease with radiographic features often restricted to the epiphyses of the long bones. PSACH and some forms of MED result from mutations in cartilage oligomeric matrix protein (COMP), a pentameric glycoprotein found in cartilage, tendon, ligament and muscle. PSACH-MED patients often have a mild myopathy characterized by mildly increased plasma creatine kinase levels, a variation in myofibre size and/or small atrophic fibres. In some instances, patients are referred to neuromuscular clinics prior to the diagnosis of an underlying skeletal dysplasia; however, the myopathy associated with PSACH-MED has not previously been studied. In this study, we present a detailed study of skeletal muscle, tendon and ligament from a mouse model of mild PSACH harbouring a COMP mutation. Mutant mice exhibited a progressive muscle weakness associated with an increased number of muscle fibres with central nuclei at the perimysium and at the myotendinous junction. Furthermore, the distribution of collagen fibril diameters in the mutant tendons and ligaments was altered towards thicker collagen fibrils, and the tendons became more lax in cyclic strain tests. We hypothesize that the myopathy in PSACH-MED originates from an underlying tendon and ligament pathology that is a direct result of structural abnormalities to the collagen fibril architecture. This is the first comprehensive characterization of the musculoskeletal phenotype of PSACH-MED and is directly relevant to the clinical management of these patients.
authors.affiliation: Faculty of Life Sciences, Wellcome Trust Centre for Cell Matrix Research, University of Manchester, Michael Smith Building, Manchester, UK.
authors.forename: Katarzyna A
authors.initials: KA
authors.lastname: Piróg
authors.forename: Oihane
authors.initials: O
authors.lastname: Jaka
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Katakura
authors.forename: Roger S
authors.initials: RS
authors.lastname: Meadows
authors.forename: Karl E
authors.initials: KE
authors.lastname: Kadler
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Boot-Handford
authors.forename: Michael D
authors.initials: MD
authors.lastname: Briggs
mesh_terms: D000125:Achilles Tendon / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D000818:Animals; D017209:Apoptosis; D001696:Biomechanical Phenomena; D004195:Disease Models, Animal; D018450:Disease Progression; D004721:Endoplasmic Reticulum / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000172:deficiency / Q000378:metabolism; D024022:Fibrillar Collagens / Q000378:metabolism / Q000648:ultrastructure; D006023:Glycoproteins / Q000172:deficiency / Q000378:metabolism; D007150:Immunohistochemistry; D008022:Ligaments / Q000378:metabolism / Q000473:pathology; D064235:Matrilin Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018908:Muscle Weakness / Q000150:complications / Q000473:pathology; D010009:Osteochondrodysplasias / Q000150:complications* / Q000473:pathology*; D052256:Tendinopathy / Q000150:complications* / Q000473:pathology*
chemical_list: D016326:Extracellular Matrix Proteins; D024022:Fibrillar Collagens; D006023:Glycoproteins; C577540:Matn1 protein, mouse; D064235:Matrilin Proteins