Background/Purpose:

Systemic bone loss is a hallmark of rheumatoid arthritis (RA). Inflammatory cytokines such as interleukin-6 (IL-6) promote bone resorption by osteoclasts. Recent studies have shown that sphingosine-1-phosphate (S1P) controls the migration of osteoclast precursors (OCPs) between the blood and bone marrow, in part via S1P receptor 1 (S1PR1) and S1PR2 expressed on the surface of OCPs. It has been reported S1PR1 directs positive chemotaxis along an S1P gradient, and S1PR2 inhibits S1PR1 function and mediates negative chemotaxis in the direction of S1P. The purpose of this study was to investigate whether IL-6 regulates the expression of S1PR1 and S1PR2 and whether it has any influence on the localization of OCPs during the course of bone loss.

Methods:

DBA/1J mice were immunized with bovine type II collagen (Day 0 and Day 21), and anti-mouse IL-6 receptor antibody (MR16-1) was administered intraperitoneally on the same days. On Day 14 or Day 35, femurs were excised and the trabecular bone volume of the distal femur was analyzed using micro-computed tomography. The percentage of OCPs (CD11b⁺Gr-1^low+med) in the tibial bone marrow was measured by flow cytometry. S1PR1 and S1PR2 mRNA expression in OCPs from immunized mice was measured by real-time PCR. For in vitro study, OCPs were isolated from normal DBA/1J mice bone marrow by using a cell sorter, and were stimulated with IL-6. S1PR1 and S1PR2 mRNA expression in these OCPs was measured by real-time PCR. S1P-directed chemotaxis of OCPs was evaluated by using a transwell plate.

Results:

Trabecular bone volume was significantly lower in immunized mice than in non-immunized control mice on Day 35. Treatment of immunized mice with MR16-1 inhibited trabecular bone loss. The percentage of OCPs in tibial bone marrow was significantly higher and the mRNA expression of S1PR2 in OCPs was significantly higher in immunized mice than in control mice on Days 14 and 35. S1PR1 mRNA expression in OCPs from immunized mice did not differ from expression in non-immunized control mice . In MR16-1 treated mice, the percentage of OCPs and S1PR2 mRNA expression were each decreased compared with that in immunized mice on Day 14 but not on Day35. IL-6 induced S1PR2 mRNA expression in OCPs in a dose-dependent manner but did not induce S1PR1 mRNA expression. IL-6 stimulation significantly decreased S1P-directed chemotaxis of OCPs.

Conclusion:

These results demonstrate that IL-6 increases the percentage of OCPs in tibial bone marrow by upregulating S1PR2, and thereby plays a crucial role in systemic bone loss induced by inflammation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-6-promotes-systemic-bone-loss-via-upregulation-of-s1pr2-in-osteoclast-precursors-in-a-mouse-collagen-induced-arthritis-model/