Background/Purpose: In response to pro-inflammatory cytokines released locally during osteoarthritis (OA), such as the alarmins S100A8/A9, monocytes can be recruited from the bone marrow (BM) to the site of injury. Monocyte chemoattractant protein-1 (MCP-1) drives monocyte migration via binding with C-C chemokine receptor type 2 (CCR2). In mice, two functionally distinct monocyte populations are described: pro-inflammatory Ly6C-high monocytes (CCR2^high) and patrolling Ly6C-low monocytes (CCR2^low). The objectives of our study are to investigate the systemic effects of locally induced OA on BM monocyte populations and their recruitment to the OA joint in collagenase induced OA (CiOA), and the involvement of S100A8/A9 herein.

Methods: CiOA was induced by unilateral-articular collagenase-injection in C57BL/6 mice. At day 7, 21 and 42, mice were sacrificed together with age-matched saline-injected control mice (n=6/group), and expression of several pro-inflammatory cytokines, and MCP-1 and CCR2 were measured in the synovium and serum. During CiOA and control conditions, the absolute amount of cells in the BM of the contralateral femur was measured. Cells from BM, blood and synovial tissue were isolated and analyzed by FACS. Monocyte subsets were identified as (B220/CD90/CD49b/NK1.1/Ly6G)^lowCD11b^high(F4/80/MHCII/CD11c)^low and further distinguished by their Ly6C expression. In addition, we investigated the role of S100A8/A9 on monocyte populations during early CiOA using S100A9^-/- mice.

Results: Synovial expression of the pro-inflammatory cytokines IL-1β, IL-6, TNF-α, S100A8 and S100A9 were increased at day 7, but only expression of S100A8 and S100A9 remained high until day 21. Local induction of CiOA resulted in systemic effects within the BM as shown by the significant decrease in total cell numbers at day 7 and 21 (both 14%), which decrease is suggested to be Ly6C high monocytes since the absolute amount of these cells decreases. Concurrently, relative number of Ly6C high monocytes and macrophages were significantly increased (764% and 251%, respectively) locally in the synovium at CiOA day 7, corresponding with the increased synovial mRNA expression of MCP-1 (151-fold) and CCR2 (41-fold). Since S100A8/A9 is sustainably expressed during CiOA and intra articular injection of S100A8 leads to significant induction of MCP-1 (8-fold) in the synovium, we next investigated the role of S100A8/A9 during early CiOA in more detail using S100A9^-/- mice. S100A9^-/- mice show less synovial activation, less cell influx and less cartilage degradation compared to wild type (WT) mice. Interestingly, there was no decrease in cell numbers or Ly6C high monocytes in the BM of S100A9^-/- mice. Moreover, in contrast to WT mice, the patrolling Ly6C low monocytes were significantly increased (205%) in S100A9^-/- mice, whereas the pro-inflammatory Ly6C high monocytes were not affected.

Conclusion: Local induction of OA induces systemic release of BM-derived Ly6C high monocytes, which are found subsequently increased locally in the synovium, a process that may be regulated by the sustained release of S100A8/A9 from the synovium via MCP-1.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/s100a8a9-produced-during-experimental-osteoarthritis-induces-a-systemic-decrease-in-bm-monocytes-and-increases-ly6c-high-monocytes-locally-in-the-joint/