Bone Abstracts

Genetic skeletal diseases (GSDs) are an extremely diverse and complex group of rare genetic diseases that primarily affect the development and homeostasis of the osseous skeleton. There are more than 450 unique and well-characterised phenotypes that range in severity from relatively mild to severe and lethal forms. Although individually rare, as a group of related genetic diseases, GSDs have an overall prevalence of at least 1/4000 child. Qualitative defects in cartilage structural proteins, such as collagens, proteoglycans and glycoproteins, result in a broad spectrum of both recessive and dominant GSDs.

Over the last 10 years the analysis of mouse models for COL2A1, COL10A1, MATN3, COMP, and ACAN mutations have been performed in detail, which has allowed a direct comparison of disease mechanisms. Furthermore, the application of -omics based investigations (mRNA and protein) has allowed disease signatures to be derived and either shared or discrete downstream genetic pathways to be identified. A common feature in many of these mouse models was evidence of endoplasmic reticulum (ER) stress, translating in some cases to a reduction in chondrocyte proliferation and an increase in dysregulated apoptosis in the growth plate.

Defining the relative contribution of reduced proliferation, increased and/or dysregulated apoptosis to growth plate dysplasia and reduced bone growth is experimentally challenging; however, the study of novel ‘ER-stress phenocopies’ has recently provided new insight into the specific impact of these different disease mechanisms. The cartilage-specific expression of mutant forms of thyroglobulin has confirmed that reduced chondrocyte reduction, in the absence of perturbations to apoptosis, was sufficient to cause a significant reduction in long bone growth.

In summary, recent studies using a complimentary group of genetically relevant mouse models and cartilage specific knock outs have demonstrated the key role that ER stress plays in the initiation and progression of growth plate dysplasia and reduced bone growth in a range of different GSDs. Moreover preliminary studies suggest that ER stress is therapeutic target that can be influenced through small molecule intervention.

Disclosure: The author declared no competing interests.