Project 445586

Background: Spondyloarthritis (SpA) is a common form of arthritis characterized by inflammation and new bone formation (NBF) in the spine and joint. Patients experience severe pain and restriction in mobility. Currently available treatment provides relief of symptoms in only 60% of patients and there is no definitive treatment to control NBF. Preliminary data: We discovered that macrophage migration inhibitory factor (MIF) plays a critical role on inflammation and NBF in SpA patients and animal models. We further explored the molecule that interact with MIF and found that hypoxia-inducible factor-1 alpha (HIF1a) promotes inflammation and NBF in the SpA mouse model. We observed that blocking MIF or HIF1a substantially suppresses inflammation and NBF in the animal model. Furthermore, we found common genes that regulate both MIF and HIF1a. These results indicate that the MIF/HIF axis is a potential therapeutic target in SpA. Research approach: We will confirm that HIF1a expression in SpA animal model and SpA patients' tissues is higher than in controls. Using functional assays, we will confirm how MIF and HIF interplay during inflammation and NBF. We will then test if conditional genetic deletion of HIF could prevent NBF in the SpA mouse model. Next, we will use a HIF blocker in the SpA mouse model to assess prophylactic and therapeutic effects on NBF. Finally, we will test whether modification of the identified common target genes could also be potential novel therapeutics to stop both inflammation and NBF in SpA. Research Impact: Our pilot study suggests that blocking MIF/HIF axis is a new therapeutic strategy to stop both inflammation and NBF in SpA. Given there is no currently available drug that stops both inflammation and NBF, the potential impact of this research is significant.