Uncovering Regulators of Arthritis

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Study identifies key proteins driving inflammatory disease, potential therapeutic targets.
Posted On: July 03, 2024
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Microscope image of immune cells called neutrophils (green) and a marker of inflammation, IL-23 (red), in the joints of a preclinical model of spondyloarthritis. DNA staining is in blue.

Researchers at Schroeder Arthritis Institute (Schroeder) have gained significant insights into the mechanisms underlying spondyloarthritis (SpA), an inflammatory disease that affects the spine and joints. The team identified hypoxia-inducible factor-1 alpha (HIF1A) as a key player in SpA, which promotes inflammation and other disease characteristics.

Two hallmarks of SpA are inflammation, where an overactive immune system causes pain and swelling, and new bone formation, which involves unwanted bone growth in inappropriate areas, leading to joint problems. The current therapies for SpA provide relief in only a proportion of patients and there is no cure. Moreover, there are several therapies that have failed. This raises the questions of what is really the cause of SpA and which major molecules are driving the disease process?

“Previous research from our lab identified a protein called macrophage migration inhibitory factor (MIF) as a driver of the disease that amplifies inflammation and new bone formation. However, the mechanisms behind this and the proteins that it interacts with remained largely unknown,” says Dr. Nigil Haroon, Senior Scientist at Schroeder and senior author of the study.

The research team aimed to bridge knowledge gaps in SpA disease development by identifying MIF-interacting molecules and examining the role of MIF-producing immune cells, called neutrophils, in disease progression.

“We identified HIF1A as a partner molecule physically interacting with MIF,” says Dr. Akihiro Nakamura, first author of the study and former clinical fellow in Dr. Haroon's lab. “We found that this interaction promotes inflammation and new bone formation in SpA.”

The team discovered that HIF1A increased the production and release of MIF and an inflammatory marker called IL-23 in neutrophils. Inhibiting HIF1A with a selective inhibitor reduced the expression of MIF and IL-23 and reduced the severity of arthritis and other SpA symptoms in pre-clinical models. They also found that increasing IL-23 levels induced SpA symptoms, while deletion of HIF1A and MIF suppressed IL-23-induced arthritis development, including new bone formation.

Overall, these results suggest a novel MIF/HIF1A regulatory network in SpA, functioning through immune response regulators such as IL-23.

This study offers significant insights into the mechanisms underlying spondyloarthritis and opens new avenues for treatment.

“These findings suggest that inhibiting HIF1A could be a novel therapeutic approach for treating SpA,” says Dr. Haroon, who is also head of the Division of Rheumatology at UHN and Sinai Health. “By understanding the roles of MIF and HIF1A, we can develop targeted therapies to alleviate symptoms and slow the progression of this chronic condition, improving the quality of life for patients with SpA.”

L-R: Headshots of Dr. Nakamura and Dr. Haroon

(L-R) Dr. Akihiro Nakamura, first author of the study and Dr. Nigil Haroon, senior author of the study. Both are members of the Spondyloarthritis Research and Treatment Network.

This work was supported by the Canadian Institute of Health Research, Arthritis Society (Canada), Spondyloarthritis Research and Treatment Network (SPARTAN), Spondyloarthritis Research Consortium of Canada (SPARCC), University of Toronto (U of T), Krembil Research Institute, Natural Sciences and Engineering Research Council of Canada, Canada Foundation for Innovation, Government of Ontario, National Research Foundation (NRF) of Korea, the Korea Healthy Industry Development Institute, the Krembil Foundation and UHN Foundation.

Dr. Nigil Haroon is an Associate Professor at U of T’s Institute of Medical Sciences.

Drs. Akihiro Nakamura and Nigil Haroon have filed a US provisional patent on methods of treating spondyloarthtris and Dr. Nakamura has received speaker honorarium and/or consultant fees from AbbVie, JAMP, and Novartis. Dr. Haroon has received consulting fees from AbbVie, Amgen, Eli Lilly, Janssen, Merck, Novartis and UCB.

Nakamura A, Jo S, Nakamura S, Aparnathi MK, Boroojeni SF, Korshko M, Park YS, Gupta H, Vijayan S, Rockel JS, Kapoor M, Jurisica I, Kim TH, Haroon N. HIF-1α and MIF enhance neutrophil-driven type 3 immunity and chondrogenesis in a murine spondyloarthritis model. Cell Mol Immunol. 2024 Jun 5. doi: 10.1038/s41423-024-01183-5. Epub ahead of print. PMID: 38839914.