PHI Research Team

Prevention of bone loss

Summary

We have defined several factors that inhibit osteoclast formation and wish to identify their mechanism of action and their function upon other cells in bone. This will advance knowledge about the biology of the osteoclast and mechanism to reduce bone loss.

Description

Many common diseases cause loss of bone, either locally in focal lesions, or more generally throughout the skeleton. Bone destruction is a common feature of cancers that invade bone (e.g. breast cancer) but is also seen in inflammatory diseases both chronic (e.g. rheumatoid arthritis) and in acute bacterial infections.

Central to all bone destruction in health and disease is the osteoclast cell, which is related to macrophages but is specialized to resorb (destroy) bone. Both in inflammation and in cancer, the number of osteoclasts increases greatly, resulting in bone loss. It is critical to block this bone destruction, and to do so in a way that does not impair bone formation as many current anti-osteoclastic therapies do.

Our research has focused upon the identification of novel factors that influence osteoclast formation and activity as well as understanding the processes that control how osteoclasts form and activate.

We have identified a number of new molecules that can inhibit osteoclast differentiation from haematopoietic progenitors (e.g. IL-4, IL-12, IL-18, Il-23, IL-33, sFRP-1 and OCIL) and also identified a number of therapies (anti-cancer and anti-diabetic) that unfortunately stimulate osteoclast numbers.

We are seeking to determine the mechanism by which these inhibitors and stimulators work, specifically whether they alter osteoclast progenitor commitment, and how cells of the immune system may exacerbate osteoclast formation.

Funding

National Health and Medical Research Council

Selected Publications

Kartsogiannis, V., Sims, N.A., Quinn, J.M.W., Ly, C., Cipetic, M., Poulton, I.J., Walker, E.C., Saleh, H., McGregor, N.E., Wallace, M.E., Smyth, M.J., Martin, T.J., Zhou, H., Ng, K.W. and Gillespie, M.T. (2008). Osteoclast inhibitory lectin (OCIL), an immune cell product that is required for normal bone physiology in vivo. Journal of Biological Chemistry. 283, 30850-30860.

Quinn, J.M.W., Sims, N.A., Saleh, H., Mirosa, D., Thompson, K., Bouralexis, S., Walker, E.C., Saleh, H., Martin, T.J. and Gillespie, M.T. (2008). Interleukin-23 inhibits osteoclastogenesis indirectly through lymphocytes and is required for the maintenance of bone mass in mice. Journal of Immunology. 181, 5720-5729.

Nakamura, A., Ly, C., Cipetic, M., Sims, N.A., Vieusseux, J., Kartsogiannis, V., Bouralexis, S., Saleh, H., Zhou, H., Price, J.T., Martin, T.J., Ng, K.W., Gillespie, M.T. and Quinn, J.M.W. (2007). Osteoclast inhibitory lectin (OCIL) inhibits osteoblast differentiation and function in vitro. Bone. 40, 305-315.

Sims, N.A., Jenkins, B.J., Nakamura, A., Quinn, J.M.W., Li, R., Gillespie, M.T., Ernst, M., Robb, L. and Martin, T.J. (2005). Interleukin-11 receptor signaling is required for normal bone remodeling. Journal of Bone and Mineral Research. 20, 1093-1102.

Quinn, J.M.W. and Gillespie, M.T. (2005). Modulation of osteoclast formation. Biochemical and Biophysical Research Communications. 328, 739-745.

Häusler, K.D., Horwood, N.J., Chuman, Y., Fisher, J.L., Ellis, J., Martin, T.J., Rubin, J.S. and Gillespie, M.T. (2004). Secreted frizzled-related protein-1 inhibits RANKL-dependent osteoclast formation. Journal of Bone and Mineral Research. 19, 1873-1881.