IL-17 is a proinflammatory cytokine crucial for osteoclastic bone resorption in the presence of osteoblasts or synoviocytes in rheumatoid arthritis. However, the role of IL-17 in osteoclastogenesis from human monocytes alone remains unclear. Here, we investigated the role of IL-17 in osteoclastogenesis from human monocytes alone and the direct effect of infliximab on the osteoclastogenesis induced by IL-17. Human peripheral blood mononuclear cells (PBMC) were cultured for 3 days with M-CSF. After non-adherent cells were removed, IL-17 was added with either infliximab or osteoprotegerin (OPG). Seven days later, adherent cells were stained for vitronectin receptor. On the other hand, CD11b-positive monocytes purified from PBMC were also cultured and stained as described above. CD11b-positive cells were cultured with TNF-alpha and receptor activator of NF-kappaB ligand (RANKL). In the cultures of both adherent cells and CD11b-positive cells, IL-17 dose-dependently induced osteoclastogenesis in the absence of soluble-RANKL. OPG or infliximab inhibited IL-17-induced osteoclastogenesis. Interestingly, in the culture of CD11b-positive cells, the osteoclastogenesis was more potently inhibited by infliximab than by OPG. TNF-alpha and RANKL synergistically induced osteoclastogenesis. The present study clearly demonstrated the novel mechanism by which IL-17 directly induces osteoclastogenesis from human monocytes alone. In addition, infliximab potently inhibits the osteoclastogenesis directly induced by IL-17.

This study demonstrates that IL-23 stimulates the differentiation of human osteoclasts from peripheral blood mononuclear cells (PBMC). Furthermore, in vivo blockade of endogenous IL-23 activity by treatment with anti-IL-23 antibody attenuates collagen-induced arthritis in rats by preventing both inflammation and bone destruction. IL-23 induced human osteoclastogenesis in cultures of PBMC in the absence of osteoblasts or exogenous soluble-receptor activator of NFkappaB ligand (RANKL). This IL-23-induced osteoclastogenesis was inhibited by osteoprotegerin, anti-IL-17 antibody, and etanercept, suggesting that RANKL, IL-17, and TNF-alpha are involved. In addition, we found the ratio of production levels of IL-17 to those of IFN-gamma from activated human T cells was elevated at 1 to 10 ng/ml IL-23. The inductive effect of IL-17 and the inhibitory effect of IFN-gamma on osteoclastogenesis indicate that the balance of these two cytokines is particularly important. We also demonstrated that IL-23 administered at a later stage significantly reduced paw volume in rats with collagen-induced arthritis, in a dose-dependent manner. Furthermore, anti-IL-23 antibody reduced synovial tissue inflammation and bone destruction in these rats. These findings suggest that IL-23 is important in human osteoclastogenesis and that neutralizing IL-23 after onset of collagen-induced arthritis has therapeutic potential. Thus, controlling IL-23 production and function could be a strategy for preventing inflammation and bone destruction in patients with rheumatoid arthritis.

The current study explored our hypothesis that IFN-c-producing human T cells inhibit human osteoclast formation.

Helper T (Th) cells play an important role in the pathogenesis of autoimmune diseases, including rheumatoid arthritis (RA). It has been revealed that Th17 cells can shift to Th1 cells (i.e., “nonclassic Th1 cells”), which are reported to be more pathogenic than Th17 cells per se. Thus, the association of Th cells in the pathogenesis of autoimmune disease has become more complicated. We recently reported using peripheral blood from untreated and early-onset RA patients that the ratio of CD161+Th1 cells (i.e., Th17-derived Th1 cells to CD161+Th17 cells) is elevated and that levels of interferon-γ (IFNγ)+Th17 cells are inversely correlated with levels of anti-CCP antibodies. Here, we review the plasticity of Th17 cells in the pathogenesis of RA, suggesting possible implications for novel therapies.

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Many papers have reported that osteoclasts play an important role in the pathogenesis of rheumatoid arthritis (RA); however, when we started to investigate the pathogenesis of RA, the roles of osteoclasts were not highlighted in RA bone resorption. In recent years, the number of articles on the roles of osteoclasts and interleukin (IL)-17 in the pathogenesis of RA has increased exponentially. In this review article, we describe our articles on the roles of osteoclasts and IL-17 in joint destruction in RA, from 1990 to 2011, and highlight a novel term, 'human osteoclastology', which we have used since 2008.

There are limited data in the literature concerning risk factors for incident fractures in men with rheumatoid arthritis (RA). We evaluated the association between potential risk factors and incident clinical fractures in male Japanese patients with RA. A total of 1050 male patients with RA were enrolled in a prospective, observational cohort study from 2000 to 2005. Participants were followed from 6 to 66 months (median follow-up, 48.7 months) and classified into three groups according to their incident fracture status from baseline: no new fracture, any new nonvertebral fracture, and new clinical vertebral fracture. The associations of potential risk factors were analyzed by Cox proportional hazards models. During follow-up, 30 patients (2.9%) developed a new nonvertebral fracture or a vertebral fracture. The baseline age, history of total knee replacement (TKR), and serum C-reactive protein (CRP) levels were associated with any nonvertebral fracture [baseline age: hazard ratio (HR), 1.08, 95% confidence interval (CI), 1.03-1.14; history of TKR: HR 6.02, 95% CI 1.19-30.42; and CRP: HR 0.60, 95% CI 0.38-0.95]. The baseline Japanese health assessment questionnaire (HAQ) score and daily dose of prednisolone were also associated with the incidence of clinical vertebral fractures (HR 7.74, 95% CI 2.10-28.48, and HR 1.28, 95% CI 1.14-1.45, respectively). Older age, history of TKR, and low serum CRP levels appear to be associated with any incident nonvertebral fracture in Japanese men with RA. High HAQ disability score and baseline doses of daily prednisolone may correlate with incident clinical vertebral fracture in Japanese men with RA.

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