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.