Abstract
Histamine H4 receptor (H4R) has immune-modulatory and chemotaxic effects in various immune cells. This study aimed to determine the osteoclastogenic role of H4R in rheumatoid arthritis (RA). The concentration of histamine in synovial fluid (SF) and sera in patients with RA was measured using ELISA. After RA SF and peripheral blood (PB) CD14+ monocytes were treated with histamine, IL-17, IL-21 and IL-22, and a H4R antagonist (JNJ7777120), the gene expression H4R and RANKL was determined by real-time PCR. Osteoclastogenesis was assessed by counting TRAP–positive multinucleated cells in PB CD14+ monocytes cultured with histamine, Th17 cytokines and JNJ7777120. SF and serum concentration of histamine was higher in RA, compared with osteoarthritis and healthy controls. The expression of H4R was increased in PB monocytes in RA patients. Histamine, IL-6, IL-17, IL-21 and IL-22 induced the expression of H4R in monocytes. Histamine, IL-17, and IL-22 stimulated RANKL expression in RA monocytes and JNJ7777120 reduced the RANKL expression. Histamine and Th17 cytokines induced the osteoclast differentiation from monocytes and JNJ7777120 decreased the osteoclastogenesis. H4R mediates RANKL expression and osteoclast differentiation induced by histamine and Th17 cytokines. The blockage of H4R could be a new therapeutic modality for prevention of bone destruction in RA.
Highlights
Concentration of histamine in rheumatoid arthritis (RA) and osteoarthritis patients was measured using ELISA. (b) The serum concentration of histamine in RA patients and healthy controls was measured using ELISA
The synovial fluid (SF) concentration of histamine was higher in RA patients than in osteoarthritis patients (20,639 ± 5,824 pg/ml vs 8,872 ± 1,799 pg/ml, P < 0.05, Fig. 1a)
H4 receptor (H4R) is characterized by its unique role in inflammatory, autoimmune and allergic diseases, there are still not clear studies for determination of its role in RA pathogenesis[32]
Summary
Concentration of histamine in RA and osteoarthritis patients was measured using ELISA. (b) The serum concentration of histamine in RA patients and healthy controls was measured using ELISA. Concentration of histamine in RA and osteoarthritis patients was measured using ELISA. (b) The serum concentration of histamine in RA patients and healthy controls was measured using ELISA. The mechanisms that H4R antagonist controls arthritis are reduction of pro-inflammatory cytokines and mediators, nuclear factor NF-κB, MMP-3, and a pro-inflammatory receptor, glucocorticoid-induced TNFR-related protein, while H4R antagonist increases number of blood CD4+ CD25+ FOXP3+ Treg cells, and the expression of interleukin (IL)-10 and transforming growth factor-β29, 30. One study shows the gene expression of H4R is decreased in RA synovial tissue compared with osteoarthritis, it has negative correlation with MMP-3 and serum levels of anti-cyclic citrullinated peptide antibody and C-reactive protein[31]. We determined the mediation of H4R in the histamine and Th17 cytokine-induced RANKL expression and osteoclastogenesis. We suggest the blockage of H4R could be a new therapeutic modality for prevention of bone destruction in RA patients
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