Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY.
Department of Medicine, Weill Cornell Medical College, New York, NY.
J Immunol. 2023 Nov 1;211(9):1340-1347. doi: 10.4049/jimmunol.2300317.
TNF plays a crucial role in inflammation and bone resorption in various inflammatory diseases, including rheumatoid arthritis (RA). However, its direct ability to drive macrophages to differentiate into osteoclasts is limited. Although RBP-J is recognized as a key inhibitor of TNF-mediated osteoclastogenesis, the precise mechanisms that restrain TNF-induced differentiation of macrophages into osteoclasts are not fully elucidated. In this study, we identified that the Notch ligand Jagged1 is a previously unrecognized RBP-J target. The expression of Jagged1 is significantly induced by TNF mainly through RBP-J. The TNF-induced Jagged1 in turn functions as a feedback inhibitory regulator of TNF-mediated osteoclastogenesis. This feedback inhibition of osteoclastogenesis by Jagged1 does not exist in RANKL-induced mouse osteoclast differentiation, as RANKL does not induce Jagged1 expression. The Jagged1 level in peripheral blood monocytes/osteoclast precursors is decreased in RA compared with the nonerosive inflammatory disease systemic lupus erythematosus, suggesting a mechanism that contributes to increased osteoclast formation in RA. Moreover, recombinant Jagged1 suppresses human inflammatory osteoclastogenesis. Our findings identify Jagged1 as an RBP-J direct target that links TNF and Notch signaling pathways and restrains TNF-mediated osteoclastogenesis. Given that Jagged1 has no effect on TNF-induced expression of inflammatory genes, its use may present a new complementary therapeutic approach to mitigate inflammatory bone loss with little impact on the immune response in disease conditions.
肿瘤坏死因子（TNF）在各种炎症性疾病中，包括类风湿关节炎（RA）中，发挥着关键作用，它在炎症和骨吸收中起着关键作用。然而，它直接驱动巨噬细胞分化为破骨细胞的能力有限。尽管 RBP-J 被认为是 TNF 介导的破骨细胞生成的关键抑制剂，但限制 TNF 诱导巨噬细胞分化为破骨细胞的确切机制尚未完全阐明。在这项研究中，我们发现 Notch 配体 Jagged1 是 RBP-J 的一个以前未被识别的靶点。Jagged1 的表达主要通过 RBP-J 被 TNF 显著诱导。TNF 诱导的 Jagged1 反过来作为 TNF 介导的破骨细胞生成的反馈抑制调节剂发挥作用。这种 Jagged1 对破骨细胞生成的反馈抑制在 RANKL 诱导的小鼠破骨细胞分化中不存在，因为 RANKL 不会诱导 Jagged1 的表达。与非侵蚀性炎症性疾病系统性红斑狼疮相比，RA 患者外周血单核细胞/破骨细胞前体中的 Jagged1 水平降低，提示这是导致 RA 中破骨细胞形成增加的一种机制。此外，重组 Jagged1 抑制人炎症性破骨细胞生成。我们的研究结果表明 Jagged1 是一个 RBP-J 的直接靶点，它连接了 TNF 和 Notch 信号通路，并限制了 TNF 介导的破骨细胞生成。鉴于 Jagged1 对 TNF 诱导的炎症基因表达没有影响，其应用可能为减轻炎症性骨丢失提供一种新的补充治疗方法，而对疾病状态下的免疫反应影响不大。
