Excessive osteoclast activity, which is strongly stimulated by pro-inflammatory mediators, results in bone and cartilage degeneration as central features of many arthritides. Levels of the alarmin S100A8/A9 and interleukin (IL)-1β are both increased in arthritis patients and correlate with disease activity and progression of tissue erosion. We previously presented S100A8/A9 as a good biomarker for joint inflammation and arthritis pathology under circumstances of high IL-1 signaling in mice that lack the gene encoding IL-1 receptor antagonist (Il1rn−/− mice). Here, we investigated whether S100A8/A9 is also actively involved in the development of joint inflammation and both cartilage and bone pathology under these conditions by comparing Il1rn−/− mice with mice that have an additional deficiency for S100a9 (Il1rn−/−XS100a9−/−). Il1rn−/−XS100a9−/− on a BALB/c background were obtained by crossing S100a9−/− mice and Il1rn−/− mice. Arthritis incidence and severity were macroscopically scored. Myeloid cell populations in the bone marrow and spleen were determined using flow cytometry. In vitro osteoclastogenesis of bone marrow cells was evaluated with TRAP staining. Microscopic joint inflammation, cartilage degeneration, and bone destruction were evaluated using histology of ankle joints of 12- and 20-week-old mice. Macroscopically scored arthritis severity was comparable between Il1rn−/− and Il1rn−/−XS100a9−/− mice. Inflammation, cartilage erosion, and bone erosion were clearly present in 12-week-old mice of both strains lacking Il1rn−/−, but not significantly different between Il1rn−/−XS100a9−/− and Il1rn−/−. Moreover, we observed that the numbers of neutrophils and monocytes were increased by the absence of Il1rn, which was affected by the absence of S100a9 only in the spleen but not in the bone marrow. In line with our other findings, the absence of S100a9 did not affect the osteoclastogenic potential of osteoclast precursors in the absence of Il1rn. Finally, in agreement with the findings in early arthritis development in 12-week-old mice, cartilage and bone erosion in 20-week-old mice was significantly higher in both Il1rn−/− strains, but the additional absence of S100a9 did not further affect tissue pathology. S100A8/A9 deficiency does not significantly affect inflammation and joint destruction in mice with high IL1β signaling suggesting that S100A8/A9 is not essential for the development of arthritis under these conditions.

中文翻译：

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S100A8/A9 对白细胞介素 1 受体拮抗剂敲除小鼠的炎症和关节病理发展不是必需的

由促炎介质强烈刺激的过度破骨细胞活性导致骨和软骨退化，这是许多关节炎的核心特征。关节炎患者的警报素 S100A8/A9 和白细胞介素 (IL)-1β 水平均升高，并与疾病活动和组织侵蚀进展相关。我们之前在缺乏编码 IL-1 受体拮抗剂基因的小鼠（Il1rn-/- 小鼠）中，在高 IL-1 信号传导的情况下，我们将 S100A8/A9 作为关节炎症和关节炎病理学的良好生物标志物。在这里，我们通过比较 Il1rn-/- 小鼠和 S100a9 额外缺乏的小鼠（Il1rn-/-XS100a9- /−)。通过将 S100a9-/- 小鼠和 Il1rn-/- 小鼠杂交获得 BALB/c 背景上的 Il1rn-/-XS100a9-/-。对关节炎的发病率和严重程度进行宏观评分。使用流式细胞术测定骨髓和脾脏中的髓样细胞群。用TRAP染色评估骨髓细胞的体外破骨细胞生成。使用 12 周龄和 20 周龄小鼠踝关节的组织学评估显微镜下关节炎症、软骨退化和骨破坏。Il1rn-/- 和 Il1rn-/-XS100a9-/- 小鼠之间的宏观评分关节炎严重程度相当。炎症、软骨侵蚀和骨侵蚀明显存在于两种缺乏 Il1rn-/- 的 12 周龄小鼠中，但在 Il1rn-/-XS100a9-/- 和 Il1rn-/- 之间没有显着差异。而且，我们观察到中性粒细胞和单核细胞的数量因 Il1rn 的缺失而增加，而 Il1rn 仅受脾脏中 S100a9 缺失的影响，而骨髓中则没有。与我们的其他发现一致，在没有 Il1rn 的情况下，S100a9 的缺失不会影响破骨细胞前体的破骨细胞生成潜力。最后，与 12 周大小鼠早期关节炎发展的发现一致，20 周大小鼠的软骨和骨侵蚀在两种 Il1rn-/- 菌株中显着升高，但 S100a9 的额外缺失并没有进一步影响组织病理学。S100A8/A9 缺乏不会显着影响具有高 IL1β 信号传导的小鼠的炎症和关节破坏，这表明 S100A8/A9 在这些条件下对于关节炎的发展不是必需的。