International Protease Network

School of Veterinary Science
University of Melbourne
Parkville, Victoria 3010
Email: ejmackie@unimelb.edu.au
Tel: +61-3-8344 7360
Fax: +61-3-8344 7374
Homepage:

Research

We are interested in characterising receptor-mediated responses of cells of the musculoskeletal system to proteases. We have demonstrated that the serine protease, thrombin, stimulates proliferation and inhibits differentiation of osteoblasts (bone-forming cells) and that these responses can be attributed to one of the known thrombin receptors, protease-activated receptor-1 (PAR-1). We have also demonstrated that thrombin inhibits apoptosis of osteoblasts and skeletal myoblasts; this effect is dependent on thrombin's proteolytic activity and specific for thrombin but not mediated by any of the known thrombin receptors. Current studies are aimed at identifying the mechanism of this effect. We have demonstrated that PAR-2, which is activated by a number of proteases including trypsin, matriptase, and neutrophil protease-3, is also expressed by osteoblasts and myoblasts. Our recent studies have identified a role for activation of PAR-2 in inhibiting the osteoblast-mediated differentiation of osteoclasts (bone-resorbing cells). Our current studies in this area are aimed at identifying signalling pathways that mediate this effect, as well as potential local activators of PAR-2 in bone.

Collaborations

Dr Rob Pike (Monash University, Melbourne, Victoria)
Dr James Whisstock (Monash University, Melbourne, Victoria)
A/Prof Phil Bird (Monash University, Melbourne, Victoria)
Dr Steve Bottomley (Monash University, Melbourne, Victoria)
Dr Tim Hewitson (Royal Melbourne Hospital, Melbourne, Victoria)
Dr Maria Ransjo (Department of Oral Cell Biology, Umea University, Sweden)
Prof. Er-Yuan Liao (Institute of Endocrinology and Metabolism, Xiangya Medical College, Changsha, China)

Publications

Chinni, C., de Niese, M.R., Tew, D.J., Jenkins, A.L., Bottomley, S.P. and Mackie, E.J. (1999) 'Thrombin: A survival factor for myoblasts.' J. Biol. Chem 274:9169-9174.

Jenkins, A.L., Chinni, C., de Niese, M.R., Blackhart, B. and Mackie, E.J. (2000) 'Expression of protease-activated receptor-2 during embryonic development.' Dev. Dynam. 218:465-471.

Chinni, C., de Niese, M.R., Jenkins, A.L., Pike, R.N., Bottomley, S.P. and Mackie, E.J. (2000) 'Protease-activated receptor-2 mediates proliferative responses in skeletal myoblasts.' J. Cell Sci. 113:4427-4433.

de Niese, M.R., Chinni, C., Pike, R.N., Bottomley, S.P. and Mackie, E.J. (2002) 'Dissection of protease-activated receptor-1-dependent and ?independent responses to thrombin in skeletal myoblasts.' Exp. Cell Res. 274:149-156.

Pagel, C.N., de Niese, M.R., Abraham, L.A., Chinni, C., Song, S.-J., Pike, R.N. and Mackie, E.J. (2003) 'Inhibition of osteoblast apoptosis by thrombin'. Bone 33:733-743.