Professor Michael Briggs
Professor of Skeletal Genetics

Personal biography:

  • From October 1989 to September 1992, I was a PhD Student in the MRC Clinical Research Centre at Harrow investigating the molecular defects of type I collagen in osteogenesis imperfecta.
  • From October 1992 to October 1993, I was a Research Fellow in the Division of Medical Genetics at UCLA/Cedars Sinai Medical Centre. This was a 3-year Training Fellowship in the UCLA Intercampus Medical Genetics Training Program and the project involved the genetic mapping of PSACH and MED mutations in large families with these diseases. 
  • In July 1995, I was awarded a Research Fellowship from the Arthritis Research Campaign and moved to the University of Manchester. 
  • In January 2004, I started a 5-year Wellcome Trust Senior Research Fellowship (SRF) and during this time we studied the disease mechanisms of matrilin-3 and COMP mutations in vitro and generated of the first mouse models of PSACH-MED. In April 2008, I was awarded a 5-year renewal of my SRF. 
  • In June 2012 I moved to Newcastle as Professor of Skeletal Genetics.

Overview 

During endochondral bone growth, chondrocytes in the growth plate undergo a highly coordinated and tightly controlled process of proliferation, hypertrophy and finally apoptosis at the vascular invasion front. Chondrocyte proliferation and hypertrophy is vital for correct long bone growth, whilst apoptosis of terminal hypertrophic chondrocytes plays a critical role in the transition from chondrogenesis to osteogenesis. Disruptions to these processes lead to growth plate dysplasia and result in a heterogeneous group of genetic diseases known as skeletal dysplasias that are characterised predominantly by short-limb dwarfism.

The scientific story

At each stage of maturation in the growth plate, chondrocytes synthesise and secrete specific structural proteins that are incorporated into the extracellular matrix (ECM). For example, cartilage oligomeric matrix protein (COMP) and matrilin-3 are expressed to the greatest extent by resting and proliferative chondrocytes, whilst type X collagen is expressed exclusively by hypertrophic chondrocytes. The expression of mutant forms of these cartilage structural proteins causes endoplasmic reticulum (ER) stress and induces an unfolded protein response (UPR). Briefly, the UPR is a sophisticated quality control system that aims to reduce ER stress through the activation of a number of different pathways that are mediated by three receptors, IRE1, ATF6 and PERK, and involving other downstream factors such as Xbp-1 and eIF2a. However, if ER homeostasis is not achieved then prolonged ER stress can eventually result in CHOP-mediated apoptosis.

We have shown using genetically engineered mouse models that the induction of ER stress and the UPR, through the expression of mutant COMP, matrilin-3 and type X collagen, can directly affect chondrocyte phenotype and cause growth plate dysplasia leading to short-limb dwarfism. Interestingly, although these mouse models all exhibit ER stress and an UPR, the different pathways that are activated appear to be gene and/or mutation specific. It is not clear in these archetypal examples of prolonged ER stress, whether the UPR is chondrocyte protective or a significant cause of distress. Answering this fundamental question will not only explain the initiation and progression of skeletal dysplasias, but will provide essential insight into disease mechanisms in many different diseases in which ER stress and UPR has been implicated.