Musculoskeletal Research

Musculoskeletal disorders and arthritis are the main cause of disability in Australia, affecting four million Australians and costing over $24 billion to the economy in 2007. The Musculoskeletal Research group works to identify the genetic causes of musculoskeletal disease, to understand how the responsible genes participate in musculoskeletal development and homeostasis, and to use this knowledge to improve human health. There are two main areas of research; 

Skeletal Biology & Disease

Formation of the human skeleton and the proper functioning of the bone, cartilage and joints are determined by complex interactions of developmental signalling processes. Genetic and acquired disorders affecting these tissues are common. The group’s research is aimed at understanding the molecular basis of these disorders to improve diagnosis and counselling, identify new therapeutic targets and test the effectiveness of new treatments to ultimately improve the quality of life of children with these debilitating conditions

The laboratory research program led by Professor John Bateman aims to understand the genetic basis of cartilage and bone disorders. Researchers are investigating how these mutations disturb normal tissue development and growth, using molecular and cell biology to dissect disease mechanisms in mice and cell cultures. The team is interested in how cell stress resulting from protein misfolding mutations is involved in disease and how this could be targeted with drugs to improve cellular health. The group has research programs in induced pluripotent stem cells (iPSC – stem cells generated from adult cells) in human disease modelling and the role of microRNA epigenetic regulation in joint disease.

The clinical research program led by Professor Ravi Savarirayan seeks to translate the basic research results conducted by Professor Bateman and team into tangible outcomes for patients and their families. This includes scientific confirmation of suspected clinical skeletal abnormalities, genetic counselling, offering prenatal testing where appropriate and, most importantly, in new treatment options based on better understanding of disease mechanisms. The team is current leading a world-first clinical trial into assessing the potential of a new medication in patients with achondroplasia, the most common inherited bone and cartilage condition.

Led by Dr Shireen Lamanade, the team recently discovered that the TRPV4 gene was responsible for a novel form of inherited hand osteoarthritis. TRPV4 mutations also cause developmental cartilage and bone disorders, and peripheral neuropathies. Researchers are characterising skeletal development and arthritis in TRPV4 mouse models and using human induced pluripotent stem cells (iPSC) to model the diseases in the various cell types affected to dissect the disease mechanisms.

Muscular Dystrophy

Our muscular dystrophy program focuses mainly on the most common form of muscular dystrophy, Duchenne Muscular Dystrophy, and on the disorders caused by mutations in collagen VI, Bethlem myopathy and Ullrich congenital muscular dystrophy. There is currently no cure for these disorders and no effective therapy to stop the diseases progressing to early death. Researchers are interested in understanding the pathways that are activated by the mutant or absent proteins in these diseases and how they result in muscle damage, inflammation and fibrosis so that we can target these pathways with drugs and nutraceuticals to improve patient health. 
 

Group Leaders: 
Group Members: 
Dr Jason White
Role: 
Honorary Fellow
Dr Chantal Coles
Role: 
Post-doctoral researcher
Dr Nadia Sadli
Role: 
Post-doctoral researcher
Keryn Woodman
Role: 
PhD Student
Adam Piers
Role: 
PhD Student
Chris Kintakis
Role: 
PhD Student
Sultan Alamri
Role: 
PhD Student
Emma Sanford
Role: 
PhD Student
Dr Trevor Cameron
Role: 
Research Officer
A/Prof Noel Cranswick
Role: 
Honorary Fellow
Dr Supriya Raj
Role: 
Research Coordinator
Lynn Rowley
Role: 
Research Assistant
Lisa Sampurno
Role: 
Research Assistant
Robin Forbes
Role: 
Associate Genetic Counsellor
Dr Patrick Yap
Role: 
Clinical Genetics Fellow
Prof Chris Little
Role: 
Honorary (off-site)
Dr Richard Wilson
Role: 
Honorary (off-site)
Saranga Senanayake
Role: 
Research Nurse
Deborah Clayton-Stamm
Role: 
Administrative Assistant

The cell biology of protein misfolding (ER stress) in genetic cartilage and bone disease
Many gene mutations causing inherited cartilage and bone disease have been discovered, but knowledge of the molecular basis for these mutations and ultimately how these mechanisms could be therapeutically manipulated, is only just beginning to be explored. A major laboratory research program is exploring how protein misfolding mutations cause cartilage and bone disease. The team’s research has shown these unfolded proteins can cause cellular stress and activate intracellular signalling and degradation pathways with profound effects on gene expression and cellular pathology. Researchers are exploring the molecular signalling pathways and disease mechanisms, and exploring the use of new therapeutic agents to overcome protein misfolding and cell stress.   

The use of induced pluripotential stem cells (iPSC) for functional genomic analysis of human genetic disease
The ability to generate human pluripotent stem cells from patient tissues and to differentiate these into therapeutically important cell lineages is an exciting new approach for the development of cell culture disease models and for the study of human gene function. The goal of this project is to generate patient cartilage and bone cells from blood cells and fibroblasts using induced pluripotential cell (iPSC) technology to study how human mutations cause pathology in vitro, and to test new therapeutic agents.

Understanding the molecular basis of brittle bone disease
Genetic bone disorders, such as osteogenesis imperfecta (OI), are a significant disease burden and although many mutations have been defined, the knowledge of the molecular mechanisms that cause the disease, and ultimately how these could be therapeutically manipulated, remains poorly understood. The team has developed models of the disease in vitro and in mice which are being studied to determine the effect of the mutations on cellular signalling pathways and the cell biology of how the cells respond to the mutant misfolded proteins. Understanding these events will be important for identifying new therapeutic agents.

microRNAs in arthritis
Arthritis is a major healthcare problem, costing Australia $24 billion a year in clinical care and disability. While the crucial pathology in arthritis is the progressive destruction of articular cartilage, the molecular mechanisms of the initiation and progression of cartilage destruction are not clear. microRNAs (miRNAs) are a recently discovered class of small noncoding RNAs with important roles to play in a growing number of developmental and disease situations. In these studies researchers are determining the profile of miRNA misregulation in joint tissues - cartilage, bone and synovium (soft tissue) - by studying osteoarthritis in mice. The protein targets of these osteoarthritis-specific miRNAs are being identified to uncover the structural and regulatory networks altered in this disease. These studies will provide new insights into disease mechanisms, identifying biomarkers useful in monitoring disease progression and response to treatment, and will open up new possibilities for therapeutic intervention. 

RNA surveillance – nonsense-mediated mRNA decay
mRNA surveillance nonsense mediated decay is a quality control process of cells, where aberrant mRNAs containing stop codon (nonsense) mutations are distinguished from normal mRNAs and are rapidly degraded by the cell. This process is of general importance since nonsense mutations account for around 30 per cent of all disease-causing mutations. Research on collagen X nonsense mutations in a (chondrodysplasia) has revealed a new form of surveillance with unique regulatory features, including tissue specificity. The team's current studies are exploring the mechanism of this process, how it is specified and regulated and if this form of mutant mRNA decay is involved in the surveillance of a wide range of disease genes. 

Clinical Research Project: Clinical trial to assess suitability of CNP (C-natriuretic peptide) to treat some of medical complications of achondroplasia
This trial has now enrolled 11 subjects with achondroplasia and seeks to address if a small peptide (CNP) might be safe and effective in promoting bone health and growth in patients with this condition, many of whom have severe skeletal manifestations requiring surgery. The trial is in its infancy, but is expected to run for two more years. After this a decision can be made on the effectiveness of this medication and whether more large scale trials will be rolled out. The team at MCRI has played a leading role in getting this trial started and it is the only trial centre in the southern hemisphere, with the largest number of enrolled patients.

Natural history studies
The group has been a leader in performing these studies to address the question of “What will happen to my child/me in the future?” Although seemingly a simple question, there is a lack of data regarding this in many areas of skeletal disease and without understanding the natural history of a condition, assessing the impacts of any intervention are hampered greatly. The team has conducted and has ongoing numerous studies in this area in various skeletal dysplasias.

Muscular dystrophy: identifying and evaluating new therapies
Duchenne muscular dystrophy (DMD) is a devastating childhood disorder caused by mutations in the X-linked gene DMD coding for dystrophin. DMD is the most common muscular dystrophy affecting 1:3500 males and is characterised by the absence or severe reduction of dystrophin protein in muscle, and progressive and severe muscle wasting, inflammation and fibrosis. Ullrich congenital muscular dystrophy (UCMD) is caused by mutations in collagen VI. There is currently no cure for DMD or UCMD and no effective therapy to stop the diseases progressing to early death. mRNA profiling and proteomics are being used to identifying novel pathogenic pathways and drug targets, and evaluating drugs and nutraceuticals using cell culture and mouse models.

Improving muscular dystrophy by targeting the ADAMTS5 metalloproteinase
ADAMTS5 is a metalloprotease important for extracellular matrix remodelling.  Researchers are studying the role of this enzyme in normal muscle and muscular dystrophy using mouse models, and mRNA and proteomic profiling.

The use of induced pluripotent stem cells (iPSC) for functional genomic analysis of human genetic disease
The ability to generate human pluripotent stem cells from patient tissues and to differentiate these into therapeutically important cell lineages is an exciting new approach for developing cell culture disease models to study human gene function.  The goal of this project is to generate patient cardiomycoptes, cartilage and bone cells from blood cells and fibroblasts using induced pluripotent cell (iPSC) technology to study the details of how human mutations cause muscle and skeletal pathology in vitro, and test new therapeutic agents

Promoting stop-codon read through to treat genetic disorders
Around 30% of inherited disorders are caused by mutations that introduce premature stop codons. Some of these are single base substitutions that convert an amino acid codon to a stop codon and in principle, patients with these mutations could benefit from a therapy that would allow the translating ribosomes to read through the stop codon and produce a protein with a single amino acid substitution. The goal of this project is to produce proof-of-principle and preliminary data to support a large scale screen for drugs that promote stop-codon read through. 

TRPV4 in skeletal development and arthritis
TRPV4 mutations cause skeletal dysplasias, arthritis and peripheral neuropathies.  Our studies focus on the role of TRPV4 in skeletal development and arthritis and are characterising the effect of mutations in cell culture and mouse models on TRPV4 ion channel function and responses to stimuli that activate the channel.

Funding: 
  • National Health and Medical Research Council
  • Muscular Dystrophy Australia
  • Bone Health Foundation
  • BioMarin Pharmaceutics
Collaborations: 
  • Professor Peter McIntyre, RMIT University
  • Professor Chris Little, University of Sydney
  • Dr Richard Wilson – University of Tasmania