research

arthritis & rheumatology

summary

Arthritis affects children as well as adults. In Australia, the incidence of childhood arthritis is one per 1,000 children aged two -16 years. There is no cure for arthritis and although juvenile arthritis commonly goes into remission by early adulthood, children can be left with restricted joint movement, growth defects due to steroid therapies or skeletal deformities.

In the laboratory, we are investigating molecular events that lead to the destruction of cartilage in arthritis, focusing on molecules that define cartilage structure, and the enzymes that destroy them. In the rheumatology clinic, we are participating in trials for drug therapies aimed at treating juvenile arthritis and other inflammatory disorders in children.

group leader(s)

Amanda Fosang  A/Professor Amanda Fosang
  Arthritis & Rheumatology
  Murdoch Childrens Research Institute
  Royal Children's Hospital
  Flemington Road
  Parkville
  Victoria 3052

  T +61 3 8341 6466
  F +61 8341 6429
  E   amanda.fosang@mcri.edu.au

   group leader biography

 

  Dr Jane Munro
  Arthritis & Rheumatology
  Murdoch Childrens Research Institute
  Royal Children's Hospital
  Flemington Road
  Parkville
  Victoria 3052

 T: +61 3 9345 5129
 E: jane.munro@rch.org.au

current research projects

In healthy articulating joints, cartilage lining the long bones absorbs compressive forces generated by movement and weight-bearing. An intact cartilage matrix is a cornerstone for healthy joints. The cartilage cells maintain a balance between matrix synthesis and matrix degradation, but in arthritic cartilage this balance is disturbed, causing changes in matrix metabolism, either as pathology, or an attempt at repair. In the laboratory, our goal is to understand the pathways and catabolic processes leading to cartilage degradation in health and disease.

Project 1:   How aggrecanases contribute to cartilage destruction

The molecule that provides cartilage with its ability to resist compression is aggrecan. We have engineered 'aggrecan knockin' mice, with aggrecan that resists destruction by the aggrecanase enzymes. These mice are less susceptible to aggrecan loss and cartilage erosion in both inflammatory and non-inflammatory models of arthritis and they show evidence of accelerated cartilage repair. We have also made mice with mutations to the two suspected aggrecanases, ADAMTS-4 and -5, rendering them inactive. We have shown that inactivating ADAMTS-5 alone is sufficient to arrest cartilage damage in the mouse (Nature2005). ADAMTS-5 is now a target for drug design for arthritis therapies and with that in mind, we are now working to determine how parts of the ADAMTS-5 molecule adjacent to the active site modulates ADAMTS-5 activity.

Project 2:   Mice resistant to collagen destruction

Collagen is an important structural molecule that gives cartilage its shape and tensile strength. Collagen destruction in arthritis causes irreversible cartilage damage. We have developed mice with collagen that resists destruction by 'collagenases'; these are collagenase-resistant mice. We are using experimental models of arthritis to compare cartilage pathology in these mice, with pathology in the aggrecanase-resistant mice and the ADAMTS mutant mice. This enables us to determine whether there is a role for collagenase inhibitors in addition to, or instead of, aggrecanase inhibitors, in the management of arthritis. The data currently suggests that therapies aimed at protecting the collagen scaffold in arthritis will be more effective than therapies aimed at preventing aggrecan loss alone.  Alongside the arthritis studies we have established a skeletal development program to characterise the highly abnormal growth plate in the collagenase-resistant (collagen II knockin) mouse.

Project 3:   Do fragments collagen send signals to cartilage?

Whilst working with the collagenase-resistant mice, we discovered that fragments of naturally-degraded collagen are bioactive; in other words, specific collagen fragments signal to cartilage cells that damage has been done and repair is needed. In the collagenase-resistant mice, these fragments are never made. We hypothesise that the unusual skeletal phenotype of the collagenase-resistant mice is partly due to the absence of collagen fragments and the signals that they send during growth of the skeleton. Our data show that adding purified collagen fragments to cultured cartilage cells from the collagenase-resistant mice can rescue the aberrant gene expression seen in the collagenase-resistant mice.

Project 4:   Tocilizumab in Systemic and Polyarticular-course JIA

These two studies study aim to assess the safety and efficacy of interleukin-6 blockade using the drug Tocilizumab in the management of two subtypes of Juvenile Arthritis. If proven effective, this new therapy will represent a significant therapeutic advance for these subtypes of chronic arthritis in children.

Project 5:   Weekly administered Etanercept in ERA, extended oligoarticular and psoriatic JIA

This study aims to examine the efficacy of Tumor Necrosis Factor-α blockade using weekly dosed Etanercept in three subtypes of juvenile arthritis. If proven effective, this study may lead to changes in the licensing of the drug Etanercept, which will open up new therapeutic opportunities for children with chronic arthritis.

team members

  • Jonathan Akikusa - Honorary Research Fellow
  • Roger Allen - HONORARY RESEARCH FELLOW
  • Jo Buckle - Administrative Assistant
  • Eloise Cameron - DATA ENTRY ASSISTANT
  • Nicole Davidson - Research Assistant
  • Stephanie Gauci - Postdoctoral Fellow
  • Sue Golub - RESEARCH AFFILIATE
  • Christine Hall - Technical Assistant
  • Hansen Kosasih - PhD Student (UoM Paeds)
  • Karena Last - RESEARCH AFFILIATE
  • Betty Lim - Research Assistant
  • Alissa Mcminn - Research Assistant
  • Fraser Rogerson - RESEARCH AFFILIATE
  • Heather Stanton - Postdoctoral Fellow

publications

  • Buttery JP., Lambert SB., Grimwood K., Nissen MD., Field EJ., Macartney KK., Akikusa JD., Kelly JJ., Kirkwood CD. Reduction in Rotavirus-associated Acute Gastroenteritis Following Introduction of Rotavirus Vaccine Into Australia's National Childhood Vaccine Schedule. PEDIATRIC INFECTIOUS DISEASE JOURNAL 30 (1) (2011) PubMed
  • Clarkin CE., Allen S., Wheeler-Jones CP., Bastow ER., Pitsillides AA. Reduced chondrogenic matrix accumulation by 4-methylumbelliferone reveals the potential for selective targeting of UDP-glucose dehydrogenase. MATRIX BIOLOGY 30 (3) : 163 - 168(2011) PubMed
  • Fosang AJ., Beier F. Emerging frontiers in cartilage and chondrocyte biology. Best Practice & Research Clinical Rheumatology 25 (6) : 751 - 766(2011) PubMed
  • Stanton H., Golub SB., Rogerson FM., Last K., Little CB., Fosang AJ. Investigating ADAMTS-mediated aggrecanolysis in mouse cartilage. NATURE PROTOCOLS 6 (3) : 388 - 404(2011) PubMed
  • Stanton H., Melrose J., Little CB., Fosang AJ. Proteoglycan degradation by the ADAMTS family of proteinases. BIOCHIMICA ET BIOPHYSICA ACTA 1812 (12) : 1616 - 1629(2011) PubMed

competitive funding

National Health & Medical Research Council Principal Research Fellowship (Amanda Fosang)
National Health & Medical Research Council Project Grants

collaborations & affiliations

Professor Hideaki Nagase, Imperial College, London
Professor Stefan Lohmander & Dr Andre Srtuglics, Lund University, Sweden
Dr Natalie Simms, St Vincent's Institute, Melbourne
A/Prof Chris Little, University of Sydney
Prof Eleanor Mackie, University of Melbourne
Dr Danny Chan, University of Hong Kong