Muscle weakness associated with dwarfism - it’s all connected

Pseudoachondroplasia is a dwarfing condition, primarily affecting long bones. Recently, several patients were diagnosed with a mild myopathy. Using a knock-in mouse model we show that the myopathy is specifically localised to the myotendinous junction and that it stems directly from abnormal changes to tendon.

Pseudoachondroplasia (PSACH) is an autosomal dominant skeletal dysplasia characterised by short-limbed dwarfism, joint laxity and early onset osteoarthritis (OA). It results exclusively from mutations in cartilage oligomeric matrix protein (COMP), a pentameric glycoprotein, found in cartilage, synovium, tendon, ligament and skeletal muscle. PSACH was for a long time only associated with a cartilage/bone (OA and dwarfism) and ligament (joint laxity) phenotype, however, several PSACH patients have recently been reported to neuromuscular clinics with a diagnosis of a myopathy. Subsequent biopsy and testing showed a mild myopathy with slightly increased creatine kinase levels and mild histological changes, however, the origin of the myopathy remained unknown. In this paper we have analysed in detail the tendon, ligament and skeletal muscle tissues from wild type mice and a COMP knock-in mouse mode of PSACH [1]. We have demonstrated that the mutant mice were weaker than the wild type littermates and tires easier in the standard grip strength test experiment. We have shown that COMP is expressed in all of the tissue in similar levels, however, histologically, the myopathy in mutant skeletal muscle was specifically localised to the myotendinous and perimysial junctions. These act as sites where forces are conveyed and dispersed between the muscle and tendon. Since COMP is expressed throughout the skeletal muscle and the pathology was localised specifically to the tendon attachment points, we then analysed the wild type and mutant murine tendon. We have found that the distribution of the collagen fibre diameters in tendon was shifted towards the thicker fibrils in the mutant mice. This is in agreement with a role of COMP as a catalyst of collagen fibrillogenesis and in turn resulted in altered biomechanical properties of the tissue, which was more resilient in a stretch to failure test but became more lax in a more physiologically relevant cyclic testing. We therefore conclude that the myopathy observed in the PSACH patients is specifically localised in the skeletal muscle and stems directly from the structural and biomechanical abnormalities in the tendon. Our findings are novel and may enable a better and faster diagnosis of PSACH patients and perhaps even a physiotherapy approach to alleviate some of the PSACH symptoms.

New insights into how some types of dwarfism are caused

Chondrodysplasias are common inherited skeletal disorders, and one particular type called Schmid, is caused by mutations in a collagen gene. The Boot-Handford and Briggs laboratories have now found that this disease is caused by deregulated cell metabolism rather than defective extracellular matrix.

There are many different types of dwarfisms which are caused by mutations in genes which make proteins important for bone development. Metaphyseal chondrodysplasia type schmid (MCDS) is one type of dwarfism and results from mutations within the collagen X gene. Collagen X is a protein which is made by cells and is secreted outside the cell to form an extracellular matrix.

Immunolocalisation of collagen type X in the normal and mutant mice. In the wild types mice, collagen is secreted to form an extracellular matrix. However, in the mutants, it is retained within the cells and fails to be secreted.

Proteins are made inside a cell and they have to be folded into shape before they can carry out their function. They fold in a special compartment called the endoplasmic reticulum (ER) and a mutation can alter the way a protein folds. If the protein cannot fold properly it remains inside the ER and cannot be secreted until it is correctly folded. In other words, the cells experiences “protein constipation” and the build up of unfolded proteins inside a cell causes stress to the ER. To help resolve ER stress, cells have evolved a mechanism called the unfolded protein response (UPR) which helps fold troublesome proteins into shape or be disposed of.

In many connective tissue diseases including several forms of dwarfism, mutations in genes for extracellular matrix proteins were thought to cause disease because of problems in the assembly of the extracellular matrix. However, it is becoming increasingly evident that the mutated extracellular matrix protein also has a significant effect on cellular processes, such as increasing ER stress.

To investigate the role of ER stress in the disease mechanism causing MCDS,a mouse model was generated in which ER stress was induced in the cells that produce collagen X. As a result the mice developed a dwarfism that was similar to MCDS mice. Therefore, they were able to mimic MCDS simply by causing ER stress in the right cells, thus demonstrating the importance of ER stress as a disease mechanism.

The stress caused by misfolded proteins appears to be a common element in several bone disorders and provides opportunities for the development of novel therapeutics, such as chemical “laxatives”, which aim to reduce the amount of accumulated protein in the ER and hopefully improve the clinical severity of the disease.

Louise Kung.