Factors affecting osteoblast differentiation
Parathyroid hormone (PTH) is currently the best available drug to build new bone. We have identified several osteoblast targets of PTH action and determined their ability to influence osteoblast differentiation and maturation with the view to assess these for their ability to build new bone.
Osteoporosis and other conditions that affect the skeleton (such as inflammatory bone loss, cancer-induced bone loss, and orthopaedic implant failure) are an enormous health cost burden to Australia.
Whilst there are several anti-osteolytic therapies available, the same is not true for therapies that build new bone. The only such therapy available is daily injectable parathyroid hormone (PTH), which stimulates bone formation through several poorly understood mechanisms.
Recently, therapies targeting sclerostin have proven useful in pre-clinical models, and natural genetic defects in the sclerostin / SOST gene in patients would suggest this to be a useful target. Finally, the Wnt pathway has gained much attention in the development of bone anabolic agents. However, the mechanism(s) by which the PTH, sclerostin or Wnt pathways stimulate bone formation remain obscure and warrant further investigation.
We are working on new approaches to treatments that build bone.
By investigating pathways of PTH action, we have identified new PTH targets and we are investigating their potential in treatment of osteoporosis.
We have performed gene array studies using an osteoblast-like stromal cell line to identify PTH-responsive genes in mature osteoblasts. Arrays were performed using RNA extracted at 1, 6 and 24 hours to identify immediate early, early and late genes.
This project seeks to determine the role of these PTH target genes in osteoblast differentiation and in normal bone physiology.
We are particularly focusing our attention on the role of the immediate early genes determining their effects upon osteoblast, adipocyte and osteoclast differentiation, using a variety of in vitro models (overexpression, siRNA, and retroviral delivery) and animal models where appropriate.