HSS Finds New Target for RA Drugs

Hospital for Special Surgery (HSS) researchers have identified a potential new target for drugs to treat patients with rheumatoid arthritis (RA), a protein known as IRHOM2.

“TNF can be thought of as a balloon tethered to the surface of cells. To work, it must be cut loose by signaling scissors called TACE (TNF-alpha converting enzyme), ” said Carl Blobel, M.D., Ph.D., program director of the Arthritis and Tissue Degeneration Program at HSS, in the January 25, 2013 news release. While blocking TACE could be another way to treat RA, this strategy would likely have side effects since patients lacking TACE are prone to skin infections and intestinal lesions.

Earlier this year, HSS investigators demonstrated that the TACE scissors are regulated by IRHOM1 and IRHOM2 molecules. They also demonstrated that mice that are genetically engineered to lack IRHOM2 lack functional TACE on the surface of their immune cells and don’t release TNF. These mice are healthy, and don’t develop skin or intestinal defects.

Jane Salmon, M.D., is the Collette Kean Research Chair and co-director, Mary Kirkland Center for Lupus Research at HSS, and a study author. Dr. Salmon told OTW, “We were surprised and delighted that preventing release of TNFa from myeloid cells by deleting TNFa convertase (TACE) (required to shed TNFa) only in myeloid cells or by deleting iRHOM2, we could block joint inflammation and cartilage erosion in a mouse model of arthritis. IRHOM2 regulates the activity of TACE; we show that it is critical for the development of inflammatory arthritis in mice and could represent a new drug target for RA. A promising aspect of targeting IRHOM2 is the opportunity to block TNF release specifically from cells that contribute to joint damage. Mice lacking IRHOM2 expression (or TACE expression in myeloid cells) don’t display any spontaneous pathologies, suggesting that this approach could offer safety and efficacy advantages over current anti-TNF treatments. Our study also provides a mechanistic explanation for how C5a and immune-complexes stimulate the release of TNFa: by activating IRHOM2/TACE dependent pathway.”

“With respect to the translational relevance of our work, we showed that IRHOM2 is upregulated in synovial macrophages from RA patients, and that downregulation of IRHOM2 in human macrophages by siRNA treatment blocks production of active TACE, and thus the release of TNFa. Since TNFa is a well-established mediator of RA, our findings uncover a novel approach for blocking the functions of soluble TNFa released by myeloid cells, by inhibiting IRHOM2. Because TNF is the driver of RA in human disease, as evidenced by how well anti- TNFa drugs work, we feel that our study provides a completely new angle on blocking TNFa release which implications for RA and other TNFa-dependent pathologies. We hope to develop antibodies to block IRHOM2/TACE interactions and thereby prevent release of TNFa by infiltrating inflammatory cells.”