The protective function of the Wnt inhibitor sclerostin in inflammatory bone destruction.

• Applicant: Dr. Berno Dankbar, Ph.D.
• Subject Area: Rheumatology
• Term: from 2009 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 159725117

In the past funding period, we could demonstrate that genetic deficiency or pharmacological inhibition of sclerostin led to a deterioration of disease severity in the TNFalpha-dependent arthritis mouse model (hTNFtg). hTNFtg mice that lack sclerostin or that were treated with sclerostin antibodies displayed enhanced joint inflammation, cartilage loss and bone erosion. Mechanistically, sclerostin effectively blocked TNF-induced signalling pathways, e.g. activation of p38, NFkappaB, key steps in arthritis development. Blockade appeared to involve LRP6 but was independent of the canonical Wnt-signalling pathway. Application of additional mouse models, such as the G6PI and the K/BxN serum transfer arthritis obviously revealed that the disease-promoting effect of sclerostin inhibition is dependent on the magnitide of how TNF participates in arthritis development. Our entire results obtained in the previous funding period, strongly indicates that sclerostin has a so far unknown protective role in chronic inflammation and inflammatory bone loss.These observations are of pivotal importance since inhibitors of sclerostin have been developed for the treatment of degenerative bone diseases and antibody-mediated inhibition of sclerostin is currently evaluated clinically for the treatment of postmenopausal osteoporosis in humans. Thus, it is of critical importance to investigate in more detail the role of sclerostin in inflammatory bone loss.The main objective of this project is the verification of a general protective effect of sclerostin on the TNF-dependent development of local bone erosions. For this purpose, we will compare various TNF-dependent mouse models (sclerostin knockout/antibody-treated and sclerostin-treated). For the assessment whether the lack of fibroblast-specific LRP6 is crucial for bone destruction, fibroblast-specific conditional knockouts will be compared with corresponding arthritic wt and Sost ko as well as with antibody-treated mice. The project will also include the identification and functional analyses of cytokine pathways inhibited by sclerostin in synovial fibroblasts and osteoblasts. Furthermore, the mechanism by which sclerostin/LRP6 interacts with TNFR or other cytokine receptors to inhibit signal transduction will be one of the main aspects of our project. Finally, we will investigate whether sclerostin modulates cytokine-mediated effects on proliferation, migration, apoptosis and invasive capacity of synovial fibroblasts as well as on osteoblast activity and apoptosis.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Thomas Pap