ABSTRACT
Formation of osteoclasts and consequent joint destruction are hallmarks of rheumatoid arthritis (RA). Here we show that LIGHT, a member of the tumour necrosis factor (TNF) superfamily, induced the differentiation into tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs) of CD14(+) monocytes cocultured with nurse-like cells isolated from RA synovium, but not of freshly isolated CD14(+) monocytes. Receptor activator of nuclear factor-kappaB ligand (RANKL) enhanced this LIGHT-induced generation of TRAP-positive MNCs. The MNCs showed the phenotypical and functional characteristics of osteoclasts; they showed the expression of osteoclast markers such as cathepsin K, actin-ring formation, and the ability to resorb bone. Moreover, the MNCs expressed both matrix metalloproteinase 9 (MMP-9) and MMP-12, but the latter was not expressed in osteoclasts induced from CD14(+) monocytes by RANKL. Immunohistochemical analysis showed that the MMP-12-producing MNCs were present in the erosive areas of joints in RA, but not in the affected joints of osteoarthritic patients. These findings suggested that LIGHT might be involved in the progression of inflammatory bone destruction in RA, and that osteoclast progenitors might become competent for LIGHT-mediated osteoclastogenesis via interactions with synoviocyte-like nurse-like cells.
Subject(s)
Arthritis, Rheumatoid/immunology , Monocytes/immunology , Osteoclasts/immunology , Synovial Membrane/immunology , Tumor Necrosis Factor Ligand Superfamily Member 14/physiology , Acid Phosphatase/drug effects , Acid Phosphatase/immunology , Acid Phosphatase/metabolism , Arthritis, Rheumatoid/metabolism , Bone Resorption/immunology , Bone Resorption/metabolism , Bone and Bones/drug effects , Bone and Bones/immunology , Bone and Bones/metabolism , Bone and Bones/pathology , Cathepsin K/drug effects , Cathepsin K/immunology , Cathepsin K/metabolism , Cell Differentiation/drug effects , Cell Differentiation/immunology , Cells, Cultured , Coculture Techniques , Humans , Isoenzymes/drug effects , Isoenzymes/immunology , Isoenzymes/metabolism , Matrix Metalloproteinase 12/drug effects , Matrix Metalloproteinase 12/immunology , Matrix Metalloproteinase 12/metabolism , Matrix Metalloproteinase 9/drug effects , Matrix Metalloproteinase 9/immunology , Matrix Metalloproteinase 9/metabolism , Monocytes/cytology , Monocytes/drug effects , Monocytes/metabolism , Osteoclasts/drug effects , Osteoclasts/metabolism , RANK Ligand/pharmacology , Synovial Membrane/drug effects , Synovial Membrane/metabolism , Tartrate-Resistant Acid Phosphatase , Tumor Necrosis Factor Ligand Superfamily Member 14/pharmacologyABSTRACT
SKG mice, a newly established model of rheumatoid arthritis (RA), spontaneously develop autoimmune arthritis accompanying extra-articular manifestations, such as interstitial pneumonitis. To examine possible roles of T cells for mediating this systemic autoimmunity, we generated T cell clones from arthritic joints of SKG mice. Two distinct CD8(+) clones were established and both showed in vitro autoreactivity by killing syngeneic synovial cells and a variety of MHC-matched cell lines. Transfer of each clone to histocompatible athymic nude mice elicited joint swelling and histologically evident synovitis accompanying the destruction of adjacent cartilage and bone. Notably, the transfer also produced diffuse severe interstitial pneumonitis. Clone-specific TCR gene messages in the inflamed joints and lungs of the recipients gradually diminished, becoming hardly detectable in 6-11 months; yet, arthritis and pneumonitis continued to progress. Thus, the same CD8(+) T cell clones from arthritic lesions of SKG mice can elicit both synovitis and pneumonitis, which chronically progress and apparently become less T cell dependent in a later phase. The results provide clues to our understanding of how self-reactive T cells cause both articular and extra-articular lesions in RA as a systemic autoimmune disease.
