Inhibition of calcium/calmodulin-dependent protein kinase IV in arthritis: dual effect on Th17 cell activation and osteoclastogenesis
Inhibition of calcium/calmodulin-dependent protein kinase IV in arthritis: dual effect on Th17 cell activation and osteoclastogenesis
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DOI：
10.1093/rheumatology/keac381
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发表时间：
2022-07-04
期刊：
影响因子：
5.5
通讯作者：
Tsokos, George C.
中科院分区：
文献类型：
--
作者：
Koga, Tomohiro;Umeda, Masataka;Tsokos, George C.
目的 探讨钙/钙调蛋白依赖性蛋白激酶 IV (CaMK4) 在关节炎小鼠模型和 RA 患者关节损伤发生中的作用。方法 对 Camk4 缺陷型小鼠、Camk4 (flox/flox)Lck-Cre 小鼠以及用 CaMK4 抑制剂 KN-93 或封装在标记有 CD4 或 CD8 抗体的纳米颗粒中的 KN-93 治疗的小鼠进行胶原诱导关节炎 (CIA)。记录炎症细胞因子水平、体液免疫反应、滑膜炎和 T 细胞活化。测量健康参与者和活动性 RA 患者的 CD4(+) T 细胞中的 CAMK4 基因表达。使用显微 CT 和组织学来评估关节病理学。 RA患者的CD4(+)和CD14(+)细胞分别进行Th17或破骨细胞分化。结果 CaMK4 缺陷小鼠接受 CIA 治疗后，临床评分有所改善，Th17 细胞数量减少。 KN-93 治疗通过减少炎症细胞因子的产生显着减少关节破坏。此外，Camk4 (flox/flox)Lck-Cre 小鼠和用负载 KN93 的 CD4 抗体标记纳米颗粒治疗的小鼠产生的 Th17 细胞较少，关节炎也较轻。 CaMK4 抑制可减轻 RA 患者 CD4(+) 细胞产生的 IL-17。使用CaMK4抑制剂后，RA患者体外分化的CD14(+)细胞破骨细胞数量显着减少。结论 使用全局和 CD4 细胞靶向药理学方法和条件缺陷小鼠，我们证明 CaMK4 在关节炎的发展中很重要。使用 RA 患者的离体细胞培养物，CaMK4 对于 Th17 生成和破骨细胞生成都很重要。我们认为 CaMK4 抑制代表了控制关节炎发展的新方法。
Objective To investigate the role of calcium/calmodulin-dependent protein kinase IV (CaMK4) in the development of joint injury in a mouse model of arthritis and patients with RA. Methods Camk4-deficient, Camk4 (flox/flox)Lck-Cre, and mice treated with CaMK4 inhibitor KN-93 or KN-93 encapsulated in nanoparticles tagged with CD4 or CD8 antibodies were subjected to collagen-induced arthritis (CIA). Inflammatory cytokine levels, humoral immune response, synovitis, and T-cell activation were recorded. CAMK4 gene expression was measured in CD4(+) T cells from healthy participants and patients with active RA. Micro-CT and histology were used to assess joint pathology. CD4(+) and CD14(+) cells in patients with RA were subjected to Th17 or osteoclast differentiation, respectively. Results CaMK4-deficient mice subjected to CIA displayed improved clinical scores and decreased numbers of Th17 cells. KN-93 treatment significantly reduced joint destruction by decreasing the production of inflammatory cytokines. Furthermore, Camk4 (flox/flox)Lck-Cre mice and mice treated with KN93-loaded CD4 antibody-tagged nanoparticles developed fewer Th17 cells and less severe arthritis. CaMK4 inhibition mitigated IL-17 production by CD4(+) cells in patients with RA. The number of in vitro differentiated osteoclasts from CD14(+) cells in patients with RA was significantly decreased with CaMK4 inhibitors. Conclusion Using global and CD4-cell-targeted pharmacologic approaches and conditionally deficient mice, we demonstrate that CaMK4 is important in the development of arthritis. Using ex vivo cell cultures from patients with RA, CaMK4 is important for both Th17 generation and osteoclastogenesis. We propose that CaMK4 inhibition represents a new approach to control the development of arthritis.