The role of Wif-1 and other secreted Wnt inhibitors in the control of Wnt signalling pathways during osteophyte formation

点击翻译按钮获取中文摘要

Osteophytes are bony protrusions forming on degenerating joints in osteoarthritis (OA), Psoriatic Arthritis (PsA), and Ankylosing Spondylitis (AS), but not in Rheumatoid Arthritis (RA). Osteophytes develop in a process related to endochondral ossification, which is regulated by growth factors such as Wnt factors. In RA, where osteophytes are absent, the canonical Wnt antagonist DKK1 is over-expressed. Blockade of DKK1 induces osteophyte formation in mouse arthritis, implying that canonical Wnt signalling promotes osteophyte formation. In contrast, we have shown that mice deficient in Wif-1, a Wnt antagonist interfering with both canonical and non-canonical Wnt-signalling pathways, exhibit reduced osteophyte formation in serum-induced arthritis (SIA) and in experimental OA. Thus, Wif-1 promotes osteophyte formation indicating that non-canonical Wnt signalling regulated by Wif-1may repress osteophyte formation. Moreover, we observed an aggravation of cartilage damage in Wif-1-deficient mice in these arthritis models, indicating that Wif-1 protects from arthritis-triggered cartilage degeneration. Our studies may also explain how some arthritides develop osteophytes, while others do not: Dkk1 overexpression in RA is triggered by TNFα. In contrast, we have shown that TNFα inhibits Wif-1 expression, while Wif-1 was upregulated by the osteophyte-associated cytokines IL-17 and -23. Hence, pro-inflammatory cytokines may control osteophyte formation by modulating the balance of canonical and non-canonical Wnt signalling via secreted Wnt antagonists. This research programme therefore aims to address the following questions:(i.) How does Wif-1 affect cartilage and bone alterations during arthritis?(ii.) Does Wif-1 control osteophyte formation and cartilage degradation via the regulation of non-canonical Wnt signalling pathways?(iii.) Does Wif-1 possess a therapeutic potential for the treatment of cartilage degeneration in joint diseases?(iv.) Does a disease-specific cytokine signature control the balance of canonical vs. non-canonical Wnt signalling, thereby defining the architectural phenotype of joint disease?To approve these hypotheses, the effect of Wif-1 on the mechanisms of osteophyte formation and cartilage degeneration will be investigated during SIA and experimental OA. Particularly canonical and non-canonical Wnt signalling during these processes will be studied. We will furthermore approve the hypothesis that the blockade of non-canonical Wnt signalling promotes osteophyte formation in mice with SIA. A possible therapeutical potential of ectopic Wif-1 administration in the treatment of cartilage degeneration will be evaluated in SIA and experimental OA in mice. Finally, cytokine profiles in inflammatory and degenerative joint diseases will be associated with Wnt antagonist gene expression and osteophyte formation in mice and in human patients and cytokine-dependent regulation of Wnt antagonist gene expression will be studied in vitro.