Osteoclasts (OCs) are bone-resorbing multinuclear giant cells that differentiate from mononuclear macrophage/monocyte-lineage hematopoietic precursors. Although many molecules are known to contribute to OC differentiation, RANKL chief among them, the mechanisms controlling the recruitment and homing of OC precursors (OPs) to the bone surface have not been elucidated. Here we report that sphingosine-1-phosphate (S1P) controls the movement of OPs between the blood and their site of differentiation. Cells with the properties of OPs express functional S1P1 receptors and exhibit positive chemotaxis along an S1P gradient in vitro. Intravital two-photon imaging of bone tissues revealed that a potent S1P1 agonist, SEW2871, stimulated motility of OP-containing monocytoid populations in vivo. OC/monocyte (CD11b) lineage-specific conditional S1P1 knockout mice showed osteoporotic changes due to increased OC attachment to bone surface, suggesting a crucial role of the S1P-S1P1 system in recirculation of OPs to blood where S1P levels are high. Furthermore, treatment with the S1P1 agonist FTY720 relieved ovariectomy-induced osteoporosis in mice by facilitating recirculation of OP-containing cell populations and reducing the number of mature OCs attached to the bone surface. This study provides evidence that S1P controls the migratory behavior of OPs, dynamically regulating bone mineral homeostasis, and identifies a critical control point in osteoclastogenesis that may be promising as a therapeutic target.

We demonstrated that dysbiosis increases sensitivity to arthritis via activation of autoreactive T cells in the intestine. Autoreactive SKG mouse T cells are activated by dysbiotic microbiota in the intestine, causing joint inflammation. Dysbiosis is an environmental factor that triggers arthritis development in genetically susceptible mice.

To investigate the direct role of interleukin (IL) 6 in the development of rheumatoid arthritis, IL-6-deficient (IL-6 ؊͞؊) mice were backcrossed for eight generations into C57BL͞6 mice, a strain of mice with a genetic background of susceptibility for antigen-induced arthritis (AIA). Both histological and immunological comparisons were made between IL-6-deficient (IL-6 ؊͞؊) mice and wild-type (IL-6 ؉͞؉) littermates after the induction of AIA. Although all IL-6 ؉͞؉ mice developed severe arthritis, only mild arthritis was observed in IL-6 ؊͞؊ mice. Safranin O staining demonstrated that articular cartilage was well preserved in IL-6 ؊͞؊ mice, whereas it was destroyed completely in IL-6 ؉͞؉ mice. In addition, comparable mRNA expression for both IL-1␤ and tumor necrosis factor ␣, but not for IL-6, was detected in the inf lamed joints of IL-6 ؊͞؊ mice, suggesting that IL-6 may play a more crucial role in cartilage destruction than either IL-1␤ or tumor necrosis factor ␣. In immunological comparisons, both antigen-specific in vitro proliferative response in lymph node cells and in vivo antibody production were elicited in IL-6 ؊͞؊ mice, but they were reduced to less than half of that found in IL-6 ؉͞؉ mice. Lymph node cells of IL-6 ؊͞؊ mice produced many more Th2 cytokines than did IL-6 ؉͞؉ mice with either antigen-specific or nonspecific stimulation in in vitro culture. Taken together, these results indicate that IL-6 may play a key role in the development of AIA at the inductive as well as the effector phase, and the blockade of IL-6 is possibly beneficial in the treatment of rheumatoid arthritis.

We generated a mouse line in which the src homology 2 domain–bearing protein tyrosine phosphatase (SHP)-2 binding site of gp130, tyrosine 759, was mutated to phenylalanine (gp130 F759/F759). The gp130 F759/F759 mice developed rheumatoid arthritis (RA)-like joint disease. The disease was accompanied by autoantibody production and accumulated memory/activated T cells and myeloid cells. Before the disease onset, the T cells were hyperresponsive and thymic selection and peripheral clonal deletion were impaired. The inhibitory effect of IL-6 on Fas ligand expression during activation-induced cell death (AICD) was augmented in gp130 F759/F759 T cells in a manner dependent on the tyrosine residues of gp130 required for signal transducer and activator of transcription 3 activation. Finally, we showed that disease development was dependent on lymphocytes. These results provide evidence that a point mutation of a cytokine receptor has the potential to induce autoimmune disease.

ObjectiveTo evaluate the efficacious noninferiority of subcutaneous tocilizumab injection (TCZ-SC) monotherapy to intravenous TCZ infusion (TCZ-IV) monotherapy in Japanese patients with rheumatoid arthritis (RA) with an inadequate response to synthetic and/or biologic disease-modifying antirheumatic drugs (DMARDs).MethodsThis study had a double-blind, parallel-group, double-dummy, comparative phase III design. Patients were randomized to receive TCZ-SC 162 mg every 2 weeks or TCZ-IV 8 mg/kg every 4 weeks; no DMARDs were allowed during the study. The primary end point was to evaluate the noninferiority of TCZ-SC to TCZ-IV regarding the American College of Rheumatology criteria for 20% improvement in disease activity (ACR20) response rates at week 24 using an 18% noninferiority margin. Additional efficacy, safety, pharmacokinetic, and immunogenicity parameters were assessed.ResultsAt week 24, ACR20 response was achieved in 79.2% (95% confidence interval [95% CI] 72.9, 85.5) of the TCZ-SC group and in 88.5% (95% CI 83.4, 93.5) of the TCZ-IV group; the weighted difference was −9.4% (95% CI −17.6, −1.2), confirming the noninferiority of TCZ-SC to TCZ-IV. Remission rates of the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate and the Clinical Disease Activity Index at week 24 were 49.7% and 16.4% in the TCZ-SC group and 62.2% and 23.1% in the TCZ-IV group, respectively. Serum trough TCZ concentrations were similar between the groups over time. Incidences of all adverse events and serious adverse events were 89.0% and 7.5% in the TCZ-SC group and 90.8% and 5.8% in the TCZ-IV group, respectively. Anti-TCZ antibodies were detected in 3.5% of the TCZ-SC group; no serious hypersensitivity was reported in these patients.ConclusionTCZ-SC monotherapy demonstrated comparable efficacy and safety to TCZ-IV monotherapy. TCZ-SC could provide additional treatment options for patients with RA.