Sclerostin is a potent WNT inhibitor that has been shown to protect cartilage from injury and encourage cartilage formation from cells. The therapeutic use of sclerostin is restricted by its short half-life and a limited capacity to target its effects to cartilage. With this project we propose the generation of a sclerostin mimetic, which is stabilised and targeted to cartilage cells. This will be tested for its regenerative efficacy in models of cartilage healing and cartilage formation. We will also define the molecular mechanism underpinning the homeostatic effect of sclerostin in cartilage.
Ke, H.Z., Roberts, S.J. and Holdsworth, G.  Pharmacological basis of sclerostin inhibition, ‘in’ Bilezikian, J., Martin, T.J., Clemens, T. and Rosen, C. [ed.] Principles of Bone Biology 4th Edition. Elsevier: Chapter 74.
Holdsworth, G., Roberts, S.J. and Ke, H.Z.  Novel actions of sclerostin on bone. Journal of Molecular Endocrinology 62, R167-R185.
Chang, J.C., Christiansen, B.A., Murugesh, D.K., Sebastian, A., Hum, N.R., Collette, N.M., et al.  SOST/Sclerostin Improves Posttraumatic Osteoarthritis and Inhibits MMP2/3 Expression After Injury. JBMR 33, 1105-1113.
Eldridge, S., Nalesso, G., Ismail, H., Vicente-Greco, K., Kabouridis, P., Ramachandran, M., … Dell’Accio, F.  Agrin mediates chondrocyte homeostasis and requires both LRP4 and alpha-dystroglycan to enhance cartilage formation in vitro and in vivo. Ann Rheum Dis. 75, 1228-1235.