Critical Role of LTB4/BLT1 in IL-23-Induced Synovial Inflammation and Osteoclastogenesis via NF-{kappa}B [INNATE IMMUNITY AND INFLAMMATION]

IL-23 activates the synthesis and production of leukotriene B₄ (LTB₄) in myeloid cells, which modulate inflammatory arthritis. In this study we investigated the role of LTB₄ and its receptor LTB₄R1 (BLT1) in synovial inflammation and osteoclast differentiation. Specifically, we used IL-23 in vivo gene transfer to induce arthritis in mice and showed that elevated serum LTB₄ and synovial expression of 5-lipoxygenase correlated with increased disease severity by histological evaluation and paw swelling compared with GFP gene transfer controls. To further investigate the effect of the LTB₄ pathway in bone loss, we performed osteoclast differentiation assays by stimulating with M-CSF and receptor activator of NF-B ligand bone marrow cells derived from BLT1^+/+ and/or BLT1^–/– mice and used quantitative PCR for gene expression analysis in terminally differentiated osteoclasts. Deficiency in BLT1 resulted in the upregulation of osteoclast-related genes and an increase in the formation of giant, multinucleated TRAP⁺ cells capable of F-actin ring formation. Additionally, BLT1 deficiency showed an increase of phosphorylated NF-B and phosphorylated IB levels in osteoclasts. We also performed real-time calcium imaging to study the effect of BLT1 deficiency in receptor activator of NF--B ligand–induced activation of intracellular calcium flux in vitro. Our data show that LTB₄ and its receptor BLT1 exacerbate synovial inflammation in vivo and bone resorption in vitro, suggesting that LTB₄ and BLT1 could be effectively targeted for the treatment of musculoskeletal diseases.

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