Stem Cell Medicine

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Bone & Cartilage Disorders

MCRI Stem Cell Medicine’s bone and cartilage research is conducted by the Musculoskeletal Lab, and focuses on using stem cells to produce models of inherited human cartilage and bone disorders to better understand how genetic mutations may cause disease and allow us to better explore therapies.

Research Summary

Genetic cartilage and bone disorders in children prevent normal skeletal development and function. In Australia approximately 100 babies per year are born with these debilitating conditions. The lifelong disabilities suffered by patients, which range from short stature and childhood arthritis to severe bone fragility and premature death, make these an important clinical and societal problem in their own right, but they also offer insights into more common conditions such as osteoarthritis and osteoporosis.

Until recently, investigating disease origins within human bone and cartilage has been difficult and slow, as these cells are not available from patients or controls. With the advent of induced Pluripotent Stem Cell (iPSC) technologies however, we are now able to take a patient’s skin or blood cells, turn them into stem cells, and then develop these into cartilage and bone cell disease models in the laboratory. These stem cell technologies have given us unprecedented access to bone and cartilage cells, specifically from diseased patients, to explore the causes of inherited skeletal diseases and to search for potential drug therapies. Our hope is to use these models to better understand how cartilage and bone develop and what goes wrong in genetic skeletal diseases so that we can develop treatments.

Projects

Modelling cartilage and bone collagen diseases in a dish using patient-derived stem cells

Our key research focus is to use stem cells derived from patients to produce cartilage and bone, replicating their disease in the laboratory. This work builds on our extensive experience in figuring out gene mutations, particularly in the collagen genes, that are a major cause of genetic skeletal disease. We also have expertise in unravelling the protein consequences of disease causing mutations. Until recently, our understanding of disease cause and progression has been limited by the need to use mouse models or to work with transfected cells. With stem cell technology advancements however, our lab has created state of the art methods known as ‘protocols’ to develop iPSCs into the bone and cartilage cells required for our research. We are continuing to optimise these protocols and are using them to identify how cartilage and bone development are disturbed by genetic mutations within collagen, searching for new therapies and treatments for patients.

Modelling TRPV4 cartilage diseases using stem cells

The TRPV4 gene plays an important role in the human body, as among other things, it senses changes in the environment around cells and controls calcium entry into cells. Inside the cell calcium is a crucial signalling molecule, telling the cell how to respond to the extracellular environment. In cartilage TRPV4 senses biomechanical forces, for example, changes in pressure in knee cartilage when we walk, run or jump. Genetic mutations in the TRPV4 gene can cause a spectrum of skeletal disorders ranging from premature hand and foot arthritis, to severely debilitating skeletal malformation. In our laboratory, we are creating models of these disorders using iPSCs, developing them into cartilage cells in order to explore how a patient’s TRPV4 mutations impact their proteins’ ability to create healthy cartilage within the body, and how the mutations change the way TRPV4 responds to changes in the cellular environment. We can now use these models to find ways to modify the behaviour of the malfunctioning proteins and search for suitable treatments.

microRNAs as therapeutic targets for osteoarthritis

Using a mouse model of post-injury osteoarthritis (the kind of arthritis that results from sports injuries) we have identified signature microRNA gene expression changes that are associated with disease. In this project we are using state of the art gene editing technology to knock out these microRNAs in stem cells and our cartilage disease-in-a-dish models to determine how these microRNAs change cartilage development and influence the development of osteoarthritis.

Understanding and targeting the protein folding mechanisms that are failing in aging, cartilage-repairing cells

In this collaborative project with Prof Matt Shoulders (MIT, Massachusetts, USA), we are using our cartilage disease-in-a-dish models to explore the origins of arthritis, and pathways involved in cartilage deterioration. Chondrocytes are the cells found in cartilage, and are under constant pressure to continue producing cartilage extracellular matrix and this puts a large burden on the protein folding and secretion machinery. In this project, we are looking for ways to support cartilage cells to continue to produce the important structural proteins during aging. Our hope is that these approaches may help prevent or delay osteoarthritis.

Clinical trials in genetic cartilage disease

Clinical trials are underway on patients with genetic cartilage disease. As part of this clinical trial we plan to make iPS cells from all patients and use these to produce patient-specific cartilage cells. These disease-in-a-dish models will be used to determine the disease mechanisms in each patient and to test the effectiveness of the trial drugs. This will allow us to correlate the clinical trial outcomes with specific mutations and mechanisms and develop targeted patient-specific precision medicine.

Key Publications

Mullan LA, Mularczyk EJ, Kung LH, Forouhan M, Wragg JM, Goodacre R, Bateman JF, Swanton E, Briggs MD, Boot-Handford RP. Increased intracellular proteolysis reduces disease severity in an ER stress-associated dwarfism. J Clin Invest. 2017 127(10):3861-3865.

Kung LHW, Ravi V, Rowley L, Angelucci C, Fosang AJ, Bell KM, Little CB, Bateman JF. Cartilage MicroRNA Dysregulation During the Onset and Progression of Mouse Osteoarthritis Is Independent of Aggrecanolysis and Overlaps With Candidates From End-Stage Human Disease. Arthritis Rheumatol. 2018 70(3):383-395. 

Gandolfi B, Alamri S, Darby WG, Adhikari B, Lattimer JC, Malik R, Wade CM, Lyons LA, Cheng J, Bateman JF, McIntyre P, Lamandé SR, Haase B. A dominant TRPV4 variant underlies osteochondrodysplasia in Scottish fold cats. Osteoarthritis Cartilage. 2016 24(8):1441-50.

Cameron TL, Bell KM, Gresshoff IL, Sampurno L, Mullan L, Ermann J, Glimcher LH, Boot-Handford RP, Bateman JF. PXBP1-Independent UPR Pathways Suppress C/EBP-β Mediated Chondrocyte Differentiation in ER-Stress Related Skeletal Disease. LoS Genet. 2015 11(9):e1005505.

Cameron TL, Gresshoff IL, Bell KM, Piróg KA, Sampurno L, Hartley CL, Sanford EM, Wilson R, Ermann J, Boot-Handford RP, Glimcher LH, Briggs MD, Bateman JF. Cartilage-specific ablation of XBP1 signaling in mouse results in a chondrodysplasia characterized by reduced chondrocyte proliferation and delayed cartilage maturation and mineralization. Osteoarthritis Cartilage. 2015 23(4):661-70. 

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. Mutations in TRPV4 cause an inherited arthropathy of hands and feet. Nat Genet. 2011 43(11):1142-6. 

Laboratory Contacts

Joint Group Leaders

Research Officers

Research Assistants

PhD Students

Masters Students

Clinical Trials Principal Investigator

Clinical Trials Coordinator