NF-κB–inducing kinase controls lymphocyte and osteoclast activities in inflammatory arthritis

• Published in: The Journal of clinical investigation Vol. 115; no. 7; pp. 1848 - 1854
• Main Authors: Aya, Kunihiko, Alhawagri, Muhammad, Hagen-Stapleton, Amanda, Kitaura, Hideki, Kanagawa, Osami, Veis Novack, Deborah
• Format: Journal Article
• Language: English
• Published: American Society for Clinical Investigation 01.07.2005
• ISSN: 0021-9738
• DOI: 10.1172/JCI23763

NF-κB is an important component of both autoimmunity and bone destruction in RA. NF-κB–inducing kinase (NIK) is a key mediator of the alternative arm of the NF-κB pathway, which is characterized by the nuclear translocation of RelB/p52 complexes. Mice lacking functional NIK have no peripheral lymph nodes, defective B and T cells, and impaired receptor activator of NF-κB ligand–stimulated osteoclastogenesis. We investigated the role of NIK in murine models of inflammatory arthritis using Nik–/– mice. The serum transfer arthritis model is initiated by preformed antibodies and required only intact neutrophil and complement systems in recipients. While Nik–/– mice had inflammation equivalent to that of Nik+/+ controls, they showed significantly less periarticular osteoclastogenesis and less bone erosion. In contrast, Nik–/– mice were completely resistant to antigen-induced arthritis (AIA), which requires intact antigen presentation and lymphocyte function but not lymph nodes. Additionally, transfer of Nik+/+ splenocytes or T cells to Rag2–/– mice conferred susceptibility to AIA, while transfer of Nik–/– cells did not. Nik–/– mice were also resistant to a genetic, spontaneous form of arthritis, generated in mice expressing both the KRN T cell receptor and H-2 g7 . Thus, NIK is important in the immune and bone-destructive components of inflammatory arthritis and represents a possible therapeutic target for these diseases.