Musculoskeletal
Understand the genetic basis for cartilage, bone and muscle disorders, characterise how mutations change cell behaviour and signalling pathways and identify and test new therapies.
Human skeletal development and bone, cartilage and joint function are determined by complex interactions of developmental signalling processes. Genetic and acquired disorders affecting these tissues are common and targeted therapies to treat these disorders are not available. Our research aims to understand 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 is led by Assoc Prof Shireen Lamandé and Professor John Bateman and 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 using induced pluripotent stem cells (iPSCs – stem cells generated from adult cells) to model human genetic disease in the lab and test potential new therapies before progressing promising new drug therapies into pre-clinical testing in mouse models. Researchers are seeking to understand the role of microRNA epigenetic regulation in joint disease, and to generate iPSC-derived cartilage for tissue repair.
Our projects
Modelling human skeletal disease using induced pluripotent stem cells (iPSCs)
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.
Protein misfolding (ER stress) in genetic cartilage and bone disease
Many gene defects that cause inherited cartilage and bone disease have been discovered, but how these mutations cause disease and how the disease 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 cell 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 testing new therapeutic agents to overcome protein misfolding and cell stress.
Tissue engineering using iPSC-derived chondrocyte organoids to repair articular cartilage damage
Osteoarthritis is caused by erosion of articular cartilage surfaces, critical for joint function. Current tissue regeneration approaches are inadequate. This project is evaluating the use of human pluripotent stem cells to produce high-quality living cartilage for use in cartilage repair. Our new approach for cartilage tissue regeneration is to use a novel method we have developed that directs human pluripotent stem cells to form high-quality cartilage with the specific biochemical and mechanical qualities of the articular cartilage and the underlying cartilage zones. These human cartilage organoids will be transplanted into cartilage defects in a rat cartilage repair model.
Funding
- National Health and Medical Research Council
Collaborations
- Dr Elizabeth Ng, Murdoch Children's Research Institute
- Prof Matthew Shoulders, MIT (USA)
- Prof Luke Wiseman, Scripps Research (USA)
- Prof Christopher Little, University of Sydney
- Prof Natalie Sims, St Vincent’s Institute of Medical Research
- A/Prof Kathryn Stok, University of Melbourne
- Prof Karl Kadler, University of Manchester (UK)
Featured publications
- Mullan LA, Mularczyk EJ, Kung LH, Bateman JF, Swanton E, Briggs MD, Boot-Handford RP (2017) Increased intracellular proteolysis reduces disease severity in an ER stress-associated dwarfism J Clin Invest 127:3861-3865. https://pubmed.ncbi.nlm.nih.gov/28920921/
- Bateman JF, Sampurno L, Maurizi A, Lamandé SR, Sims NA, Cheng TL, Schinderler A, Little DG (2019) Effect of rapamycin on bone mass and strength in the a2(I)-G610C mouse model of osteogenesis imperfecta J Cell Molec Med 23:1735-1745. https://pubmed.ncbi.nlm.nih.gov/30597759/
- Lamandé, SR, Yuan, Y, Gresshoff, IL, Rowley, L, Belluoccio, D, Kaluarachchi, K, Little, CB, Botzenhart, E, Zerres, K, Amor, DJ, Cole WG, Savarirayan, R, McIntyre, P, Bateman, JF (2011) Mutations in TRPV4 cause an inherited arthropathy of hands and feet. Nature Genetics 43, 1142-1146. https://pubmed.ncbi.nlm.nih.gov/21964574/
- Dudek M, Angelucci C, Pathiranage D, Wang P, Mallikarjun V, Lawless C, Swift J, Kadler KE, Boot-Handford RP, Hoyland JA, Lamandé SR, Bateman JF, Meng Q-J. (2021) Circadian time series proteomics reveals daily dynamics in cartilage physiology. Osteoarthritis Cartilage 29:739-749. https://pubmed.ncbi.nlm.nih.gov/33610821/
- Kung LHW, Ravi V, Rowley L, Angelucci C, Fosang AJ, Bell KM, Little CB, Bateman JF (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 Arth Rheum 70: 383-395. https://pubmed.ncbi.nlm.nih.gov/29145712/