Research outline - Orthopaedic Research and Biotechnology Unit
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Research program
Established research projects
Bisphosphonates as therapeutics for paediatric orthopaedics
Bisphosphonates (BPs) are a class of anti-resorptive drugs that were originally developed for the treatment of osteoporosis. We speculated that the fundamental source of the pathology in some orthopaedic conditions may be due to excessive bone resorption. In these cases, BP therapies may be advantageous. Our work in pre-clinical models now forms a key portion of the literature. Bisphosphonates are increasingly used in orthopaedics for the treatment of genetic and metabolic bone diseases. There are orthopaedic indications for the use of BPs that we are continuing to investigate through our translational and clinical research programs.
Our work in bisphosphonates has led to the development of one of our main research themes– optimisation of the anabolic (bone-forming) and catabolic (bone-resorbing) responses. By combining local anabolic treatment (bone morphogenetic proteins) with systemic BP therapy, we achieved synergistic (more than additive) effects. We are continuing to explore this drug combination experimentally as well as applying it to clinical situations.
Bone defects in Neurofibromatosis type 1 (NF1)
NF1 is a common genetic disease (affecting 1 in 3000 children) that can manifest as a variety of characteristic symptoms including prevalent tumour formation. These children can also develop severe orthopaedic problems, including scoliosis (curvature of the spine) and a congenital tibial dysplasia. Orthopaedic surgery on NF1 children has a poor prognosis due to underlying problems with bone healing.
We have been using genetic mouse models of NF1 deficiency, as well as studies with NF1 patients treated at the Children's Hospital at Westmead to explore the mechanism of these bone defects. Our ongoing research is funded by both the National Health & Medical Research Council (www.nhmrc.gov.au) and the Children's Tumor Foundation (www.ctf.org). We have published studies that indicate that dual problems in bone anabolism and bone catabolism may both contribute to the NF1 bone phenotype.
The role of muscle in bone repair
It is not uncommon for bone to form in abnormal locations, and muscle is the most common site for this to occur. Our research has shown that muscle stem cells have a strong innate capacity to form bone, and we hypothesize that muscle cells may be actively recruited for bone healing.
In this NH&MRC-funded project, we are investigating the contribution of muscle cells to fracture repair using a combination of cell culture and genetic mouse models. As well as revealing key insights into the cellular contributions to bone formation and repair, this project may result in new cell-based therapies for bone repair that utilise muscle cells.
The role of osteoclasts in fracture repair
The majority of fractures heal via the process of endochondral ossification, where cartilage acts as a precursor to the primary ossification event. The conventional dogma purports that osteoclasts are the cells responsible for the removal of cartilage prior to bone formation. However, we have found in models of osteoclast inhibition or dysfunction, the early stages of fracture repair progress normally.
We are currently investigating the effects of anti-osteoclastic agents on the early stages of fracture repair. We are also testing the effects of agents that disrupt the action of matrix metalloproteases (MMPs), enzymes secreted by a range of cell types that may also contribute to matrix degradation and cartilage resorption.
Emerging research directions
Human orthopaedic cell & tissue bank
Following review by our institutional ethics committee, in 2007 we commenced collection of samples from patients with and without genetic bone disease who are undergoing surgery. Bone cells can be isolated, grown, and cryo-stored in the laboratory for future research efforts. These specimens will be an invaluable aid for the future translation of our pre-clinical studies.
Sclerostin and fracture healing
Sclerostin is a recently discovered molecule secreted by osteocytes. Osteocytes are cells within bone that are critical for the regulation of bone mass, and genetic defects in Sclerostin have been linked to high-bone mass diseases. Sclerostin-based therapies are currently being developed for osteoporosis, however the normal and potential therapeutic role for Sclerostin in orthopaedics remains unclear.
In an emerging collaborative effort with scientists the Children's Medical Research Institute, as well as commercial biotech interests, we are examining the orthopaedic actions of Sclerostin as well as its associated signalling molecules.
Novel therapeutics for orthopaedic medicine
In collaboration with several international pharmaceutical companies, we are currently testing several compounds for their efficacy in treatment of orthopaedic complications. These drugs have the potential to revolutionize orthopaedic medicine. We have established surgical models and high-tech scanning, histology, and molecular outcomes for testing these drugs.
Research support (2008/09)
Modulation of bone healing using the Neuropeptide Y system
Baldock P, Little D G
NHMRC Grant 535932 ($487,000 over 3 years)
Modelling the loss of NF1 heterozygosity in congenital pseudarthrosis of the tibia (CPT)
Little D G, Baldock P, Alexander I, Schindeler A
NHMRC Grant 512245 ($462,000 over 3 years)
The Role of Muscle Cells in Bone Repair
Little D G, Schindeler A
NHMRC Grant 457244 ($267,200 over 2 years)
Role of the Osteoclast in Endochondral Fracture Repair
Little D G, Munns C F
NHMRC Grant 402714 ($300,250 over 3 years)
Muscle Cell Contribution to Bone Repair
Little D G, Birke O, Schindeler A
AOA Research Foundation ($38,500 over 2 years)
Novel Scaffolds for Repairing Bone Defect
Little D G, Zreiqat H
AOA Research Foundation ($58,658 over 1 year)
Bone Health in NF1
Simm P, Munns C F, North K, Cowell C, Little D G, Schindeler A, Baldock P
Pfizer Endocrine Care Paediatric Research Grant ($55,000 over 1 year)
Industry supported project: "Sclerostin in bone repair"
AMGEN ($381,674 over 2 years)
Industry supported project: "Sclerostin in bone repair"
Novartis AG ($225,939 over 2 years)
Industry supported project: "Zoledronic Acid in Steroid Induced Osteoporosis"
Novartis AG ($200,000 over 2 years)
Industry supported project: "Orthopaedic Applications for Bisphosphonates"
Novartis AG ($677,000 over 6 years)
