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.

Abnormal bone quality in cartilage oligomeric matrix protein and matrilin 3 double‐deficient mice caused by increased tissue inhibitor of metalloproteinases 3 deposition and delayed aggrecan degradation

“…The size reduction seen in our double-mutant animals may indicate that this phenotype occurs at least partly as a result of the lack of the protein and not only as a result of the increased apoptosis of growth plate chondrocytes, as has been reported in animals carrying mutations that cause multiple epiphyseal dysplasia (30,31). The reduction in bone length in COMP/matrilin 3 double-deficient animals was associated with abnormal bone quality due to delayed aggrecan degradation and altered replacement of cartilage by bone in the metaphyseal trabeculae (Figure 2A).…”

“…We report herein that COMP/matrilin 3 double-deficient mice showed normal skeletal development as newborns (Figure 1), but displayed altered cartilage and bone remodeling at later stages of development (Figure 2), which was initially observed as a reduction in body length and long bone length. Interestingly, knockin mice for either COMP or matrilin 3 carrying mutations that cause chondrodysplasia in humans showed a similar reduction in bone length (30,31). The phenotype of such knockin mice is similar to that seen in multiple epiphyseal dysplasia in humans, but only in animals homozygous for the mutation, which is different from the autosomal-dominant inheritance in humans.…”

COMP-assisted collagen secretion - a novel intracellular function required for fibrosis

“…Most of the disease-causing mutations have been shown to result in misfolding of COMP, leading to retention and accumulation of the mutant protein in the secretory pathway (Dinser et al, 2002;Hecht et al, 1998;Hou et al, 2000;Kleerekoper et al, 2002). Other mutations in COMP still allow secretion but seem to cause an inappropriate ECM assembly (Pirog et al, 2010).…”

Antisense Reduction of Mutant COMP Reduces Growth Plate Chondrocyte Pathology

“…This is further supported by the minimal chondrocyte pathology observed in two knockin COMP mutation mouse models that do not completely recapitulate PSACH chondrocyte pathology and clinical manifestations. [50][51][52][53] Altogether, this suggests that the total amount of COMP is an important factor in MT-COMP pathology and that reduction of total COMP with ASOs ameliorates the disease process.…”

“…This is further supported by the minimal chondrocyte pathology observed in two knockin COMP mutation mouse models that do not completely recapitulate PSACH chondrocyte pathology and clinical manifestations. [50][51][52][53] Altogether, this suggests that the total amount of COMP is an important factor in MT-COMP pathology and that reduction of total COMP with ASOs ameliorates the disease process.We show that mitigation of the chondrocyte pathology was achieved by administering ASO1 for 3 weeks at 180 mg/kg/week. This level of COMP knockdown (38% hCOMP and 60% mCOMP) reduced intracellular retention of MT-COMP, chondrocyte death, and inflammatory markers and partially restored normal levels of chondrocyte proliferation ( Figures 5B-5J and 6).…”