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.
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.
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.
- Ablation of Grb10 Specifically in Muscle Impacts Muscle Size and Glucose Metabolism in Mice. 2018
- Cartilage MicroRNA Dysregulation During the Onset and Progression of Mouse Osteoarthritis Is Independent of Aggrecanolysis and Overlaps With Candidates From End-Stage Human Disease. 2018
- Diagnosis of lethal or prenatal-onset autosomal recessive disorders by parental exome sequencing. 2018
- Temporal Lobe Malformations in Achondroplasia: Expanding the Brain Imaging Phenotype Associated withFGFR3-Related Skeletal Dysplasias. 2018
- Best practices in peri-operative management of patients with skeletal dysplasias. 2017
- Collagen VI disorders: Insights on form and function in the extracellular matrix and beyond. 2017
- Comprehensive Expression Analysis of microRNAs and mRNAs in Synovial Tissue from a Mouse Model of Early Post-Traumatic Osteoarthritis. 2017
- Diagnostic Impact and Cost-effectiveness of Whole-Exome Sequencing for Ambulant Children With Suspected Monogenic Conditions. 2017
- Impaired engagement of the ventral attention system in neurofibromatosis type 1. 2017
- Increased intracellular proteolysis reduces disease severity in an ER stress-associated dwarfism. 2017
- Monoallelic and biallelic CREB3L1 variant causes mild and severe osteogenesis imperfecta, respectively. 2017
- Monoallelic BMP2 Variants Predicted to Result in Haploinsufficiency Cause Craniofacial, Skeletal, and Cardiac Features Overlapping Those of 20p12 Deletions. 2017
- Risk assessment in paediatric glioma-Time to move on from the binary classification. 2017
- Successful Use of Enzyme Replacement Therapy in Infantile Hypophosphatasia. 2017
- The intervertebral disc contains intrinsic circadian clocks that are regulated by age and cytokines and linked to degeneration. 2017
- Utility of circulating serum miRNAs as biomarkers of early cartilage degeneration in animal models of post-traumatic osteoarthritis and inflammatory arthritis. 2017
- A Disintegrin and Metalloproteinase with Thrombospondin Motifs-5 (ADAMTS-5) Forms Catalytically Active Oligomers. 2016
- A dominant TRPV4 variant underlies osteochondrodysplasia in Scottish fold cats. 2016
- Biallelic FANCD1/BRCA2 mutations predisposing to glioblastoma multiforme with multiple oncogenic amplifications. 2016
- Carboplatin Hypersensitivity Reactions in Pediatric Low Grade Glioma Are Protocol Specific and Desensitization Shows Poor Efficacy. 2016
- Cystatin C Based Equation Accurately Estimates Glomerular Filtration Rate in Children With Solid and Central Nervous System Tumours: Enough Evidence to Change Practice? 2016
- Diagnosis and etiology of congenital muscular dystrophy: We are halfway there. 2016
- Disseminated glioneuronal tumors occurring in childhood: treatment outcomes and BRAF alterations including V600E mutation. 2016
- GAPTrap: A Simple Expression System for Pluripotent Stem Cells and Their Derivatives. 2016
- Low rates of recurrence and slow progression of pediatric pilocytic astrocytoma after gross-total resection: justification for reducing surveillance imaging. 2016
- Mutations in CDC45, Encoding an Essential Component of the Pre-initiation Complex, Cause Meier-Gorlin Syndrome and Craniosynostosis. 2016
- Novel Elements of the Chondrocyte Stress Response Identified Using an in Vitro Model of Mouse Cartilage Degradation. 2016
- Nutraceuticals and Their Potential to Treat Duchenne Muscular Dystrophy: Separating the Credible from the Conjecture. 2016
- Randomized placebo-controlled study of lovastatin in children with neurofibromatosis type 1. 2016
- Response: "Best practices in the evaluation and treatment of foramen magnum stenosis in achondroplasia during infancy" and "is there a correlation between sleep disordered breathing and foramen magnum stenosis in children with achondroplasia?" 2016
- Single agent carboplatin for pediatric low-grade glioma: A retrospective analysis shows equivalent efficacy to multiagent chemotherapy. 2016
- Aberrant mitochondria in a Bethlem myopathy patient with a homozygous amino acid substitution that destabilizes the collagen VI a2(VI) chain. 2015
- Best practices in the evaluation and treatment of foramen magnum stenosis in achondroplasia during infancy. 2015
- Breeding Strategy Determines Rupture Incidence in Post-Infarct Healing WARPing Cardiovascular Research. 2015
- Cartilage-specific ablation of XBP1 signaling in mouse results in a chondrodysplasia characterized by reduced chondrocyte proliferation and delayed cartilage maturation and mineralization. 2015
- Catabolic cytokines disrupt the circadian clock and the expression of clock-controlled genes in cartilage via an NF?B-dependent pathway. 2015
- Long-term visual outcome after chemotherapy for optic pathway glioma in children: Site and age are strongly predictive. 2015
- Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type. 2015
- Nosology and classification of genetic skeletal disorders: 2015 revision. 2015
- XBP1-Independent UPR Pathways Suppress C/EBP-ß Mediated Chondrocyte Differentiation in ER-Stress Related Skeletal Disease. 2015
- A disintegrin and metalloprotease-12 is type I myofiber specific in Bos taurus and Bos indicus cattle. 2014
- Infantile haemangiomas that failed treatment with propranolol: clinical and histopathological features. 2014
- Myokines (muscle-derived cytokines and chemokines) including ciliary neurotrophic factor (CNTF) inhibit osteoblast differentiation. 2014
- The collagenopathies: review of clinical phenotypes and molecular correlations. 2014
- bfb, a Novel ENU-Induced blebs Mutant Resulting from a Missense Mutation in Fras1. 2013
- Characterization of the core clinical phenotype associated with recurrent microdeletion of 15q25.2 2013
- Comparative Proteomic Analysis of Normal and Collagen IX Null Mouse Cartilage Reveals Altered Extracellular Matrix Composition and Novel Components of the Collagen IX Interactome. 2013
- Hyaluronan Synthesis and Myogenesis A REQUIREMENT FOR HYALURONAN SYNTHESIS DURING MYOGENIC DIFFERENTIATION INDEPENDENT OF PERICELLULAR MATRIX FORMATION 2013
- Maintaining mRNA Integrity during Decalcification of Mineralized Tissues. 2013
- Mechanistic insight into the pathology of polyalanine expansion disorders revealed by a mouse model for x linked hypopituitarism. 2013
- Natural history of pulmonary function in collagen VI-related myopathies 2013
- Nonsense-mediated mRNA decay of collagen - emerging complexity in RNA surveillance mechanisms 2013
- The Circadian Clock in Murine Chondrocytes Regulates Genes Controlling Key Aspects of Cartilage Homeostasis 2013
- The effect of height, weight and head circumference on gross motor development in achondroplasia. 2013
- Therapeutic strategies that target epigenetic, paracrine and signalling control of skeletal muscle regeneration 2013
- Transcriptomics of wild type and mice lacking ADAMTS-5 activity identifies genes involved in osteoarthritis initiation and cartilage destruction. 2013
- WARP interacts with collagen VI-containing microfibrils in the pericellular matrix of human chondrocytes. 2013
- An anti-inflammatory role for leukemia inhibitory factor receptor signaling in regenerating skeletal muscle 2012
- Autosomal dominant congenital spinal muscular atrophy: a true form of spinal muscular atrophy caused by early loss of anterior horn cells 2012
- Depletion of annexin A5, annexin A6 and collagen X causes no gross changes in matrix vesicle mediated mineralization 2012
- H-1 NMR Spectroscopy of Serum Reveals Unique Metabolic Fingerprints Associated with Subtypes of Surgically Induced Osteoarthritis in Sheep 2012
- Oral health inequalities in a national sample of Australian children aged 2-3 and 6-7 years 2012
- Parental influence and the development of dental caries in children aged 0-6 years: A systematic review of the literature 2012
- Versican Processing by a Disintegrin-like and Metalloproteinase Domain with Thrombospondin-1 Repeats Proteinases-1 and -15 Facilitates Myoblast Fusion. 2012
- Alterations in the expression of leukemia inhibitory factor following exercise: comparisons between wild-type and mdx muscles. 2011
- Cartilage Intermediate Layer Protein 2 (CILP-2) Is Expressed in Articular and Meniscal Cartilage and Down-regulated in Experimental Osteoarthritis. 2011
- Caspase-3, myogenic transcription factors and cell cycle inhibitors are regulated by leukemia inhibitory factor to mediate inhibition of myogenic differentiation 2011
- Changes in the Chondrocyte and Extracellular Matrix Proteome during Post-natal Mouse Cartilage Development. 2011
- Clinical phenotypes associated with type II collagen mutations. 2011
- Extending the scope of diagnostic chromosome analysis: Detection of single gene defects using high-resolution SNP microarrays 2011
- Human and Mouse Mutations in WDR35 Cause Short-Rib Polydactyly Syndromes Due to Abnormal Ciliogenesis 2011
- Impact of an oral health intervention on pre-school children 3 years of age in a rural setting in Australia 2011
- Increased chondrocyte sclerostin may protect against cartilage degradation in osteoarthritis 2011
- Isolated hypogonadotropic hypogonadism with SOX2 mutation and anophthalmia/microphthalmia in offspring 2011
- Loss-of-Function Mutations in PTPN11 Cause Metachondromatosis, but Not Ollier Disease or Maffucci Syndrome 2011
- Mutations in TRPV4 cause an inherited arthropathy of hands and feet. 2011
- Nosology and Classification of Genetic Skeletal Disorders: 2010 Revision 2011
- Pseudoachondroplasia and multiple epiphyseal dysplasia: a 7-year comprehensive analysis of the known disease genes identify novel and recurrent mutations and provides an accurate assessment of their relative contribution. 2011
- Recurrent dominant mutations affecting two adjacent residues in the motor domain of the monomeric kinesin KIF22 result in skeletal dysplasia and joint laxity 2011
- State-level differences in the oral health of Australian preschool and early primary school-age children 2011
- Total population investigation of dental hospitalizations in Indigenous children under five years in Western Australia using linked data 2011
- Transcriptional profiling of chondrodysplasia growth plate cartilage reveals adaptive ER-stress networks that allow survival but disrupt hypertrophy 2011
- TRPV4 related skeletal dysplasias: a phenotypic spectrum highlighted byclinical, radiographic, and molecular studies in 21 new families 2011
- Two Novel COL2A1 Mutations Associated with a Legg-Calv,-Perthes Disease-like Presentation 2011
- Two novel germline KRAS mutations: expanding the molecular and clinical phenotype. 2011
- National Health and Medical Research Council
- Muscular Dystrophy Australia
- Bone Health Foundation
- BioMarin Pharmaceutics
- Professor Peter McIntyre, RMIT University
- Professor Chris Little, University of Sydney
Dr Richard Wilson – University of Tasmania