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The utility of mouse models to provide information regarding the pathomolecular mechanisms in human genetic skeletal diseases: The emerging role of endoplasmic reticulum stress (Review)

Lookup NU author(s): Professor Michael Briggs, Dr Peter Bell, Dr Katarzyna PirogORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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 per 4,000 children. Qualitative defects in cartilage structural proteins result in a broad spectrum of both recessive and dominant GSDs. This review focused on a disease spectrum resulting from mutations in the non-collagenous glycoproteins, cartilage oligomeric matrix protein (COMP) and matrilin-3, which together cause a continuum of phenotypes that are amongst the most common autosomal dominant GSDs. Pseudoachondroplasia (PSACH) and autosomal dominant multiple epiphyseal dysplasia (MED) comprise a disease spectrum characterised by varying degrees of disproportionate short stature, joint pain and stiffness and early-onset osteoarthritis. Over the past decade, the generation and deep phenotyping of a range of genetic mouse models of the PSACH and MED disease spectrum has allowed the disease mechanisms to be characterised in detail. Moreover, the generation of novel phenocopies to model specific disease mechanisms has confirmed the importance of endoplasmic reticulum (ER) stress and reduced chondrocyte proliferation as key modulators of growth plate dysplasia and reduced bone growth. Finally, new insight into related musculoskeletal complications (such as myopathy and tendinopathy) has also been gained through the in-depth analysis of targeted mouse models of the PSACH-MED disease spectrum.

Publication metadata

Author(s): Briggs MD, Bell PA, Pirog KA

Publication type: Review

Publication status: Published

Journal: International Journal of Molecular Medicine

Year: 2015

Pages: 1483-1492

Online publication date: 30/03/2015

Acceptance date: 30/03/2015

ISSN (print): 1107-3756

ISSN (electronic): 1791-244X


DOI: 10.3892/ijmm.2015.2158