Anti‐interleukin‐6 receptor antibody prevents systemic bone mass loss via reducing the number of osteoclast precursors in bone marrow in a collagen‐induced arthritis model

Summary Systemic bone loss is a hallmark of rheumatoid arthritis ( RA ). Inflammatory cytokines such as interleukin ( IL )‐6 promote bone resorption by osteoclasts. Sphingosine‐1‐phosphate ( S 1 P ) controls the migration of osteoclast precursor cells ( OCP s) between the blood and bone marrow, in part via S 1 P receptors ( S 1 PR 1 and S 1 PR 2) expressed on the surface of OCP s. OCP s ( CD 11b + Gr ‐1 low+med ) isolated from bone marrow of DBA /1 J mice were stimulated with IL ‐6. S 1 P ‐directed chemotaxis of OCP s was evaluated using a transwell plate. mRNA expression of S 1 PR 1 and S 1 PR 2 was measured. DBA /1 J mice were immunized with bovine type II collagen (days 0 and 21) and anti‐mouse IL ‐6 receptor antibody ( MR 16‐1) was administered on days 0 and/or 21. Trabecular bone volume was analysed using micro‐computed tomography. The percentage of OCP s in tibial bone marrow and S 1 PR 1 and S 1 PR 2 mRNA expression in OCP s were measured. IL ‐6 stimulation significantly decreased S 1 P ‐directed chemotaxis of OCP s. IL ‐6 induced S 1 PR 2 mRNA expression, but not S 1 PR 1 mRNA expression, in OCP s. Bone volume was significantly lower in arthritic mice than in non‐arthritic control mice on day 35. Treatment of immunized mice with MR 16‐1 significantly inhibited bone loss. In MR 16‐1‐treated mice, the percentage of OCP s and expression of S 1 PR 2 mRNA was each decreased compared with arthritic mice on day 14, but not on day 35. IL ‐6 increased the number of OCP s in tibial bone marrow via up‐regulating S 1 PR 2, thus playing a crucial role in systemic bone loss induced by inflammation.