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

Kunihiko Aya, Muhammad Alhawagri, Amanda Hagen-Stapleton, Hideki Kitaura, Osami Kanagawa, Deborah Veis Novack

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

Abstract

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 Nk -/- 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-2g7. Thus, NIK is important in the immune and bone-destructive components of inflammatory arthritis and represents a possible therapeutic target for these diseases.

Original languageEnglish
Pages (from-to)1848-1854
Number of pages7
JournalJournal of Clinical Investigation
Volume115
Issue number7
DOIs
StatePublished - Jul 2005

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