Leukemia inhibitory factor is dysregulated in ankylosing spondylitis and contributes to bone formation
Leukemia inhibitory factor is dysregulated in ankylosing spondylitis and contributes to bone formation
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DOI：
10.1111/1756-185x.14312
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发表时间：
2022-03-03
影响因子：
2.5
通讯作者：
Yan, Xiaoping
中科院分区：
文献类型：
--
作者：
Kong, Weiping;Tang, Yulong;Yan, Xiaoping
目的 强直性脊柱炎（AS）是一种慢性炎症性疾病。然而，这种疾病中被破坏的关键炎症细胞因子尚未明确定义。在本研究中，我们进行了蛋白质阵列和多种蛋白质定量，以研究 AS 患者和健康受试者血浆中差异表达的细胞因子。方法 在发现队列中，5 名从未接受过生物治疗的 AS 患者和 5 名性别和年龄匹配的健康受试者被纳入蛋白质芯片分析。在验证阶段另外招募了 40 名 AS 患者和 20 名健康参与者。此外，在体外成骨细胞模型中对 hFOB1.19 细胞中成骨相关基因的信使 RNA 和蛋白质水平进行了定量。结果 在蛋白质阵列发现差异表达的 318 种细胞因子中，与对照组相比，AS 患者的白血病抑制因子 (LIF) 显着增加。 “白细胞介素信号传导”通路是AS患者中最丰富的通路，“白细胞介素信号传导”相关细胞因子，包括LIF、白细胞介素（IL）-6、IL-23和IL-31，在验证阶段表达显着差异。此外，我们将 AS 患者中 LIF 的表达与 C 反应蛋白 (CRP) 和脊柱磁共振成像病变 (MRI-SPINE) 的炎症相关联。我们进一步分析了LIF在hFOB细胞中的作用，发现LIF在蛋白水平上促进生长因子受体结合蛋白2/磷酸细胞外信号调节激酶/runt相关转录因子2/碱性磷酸酶通路，并激活多个成骨相关基因（RUNX2和BGLAP）。结论 AS患者血浆中LIF较健康受试者升高，且与AS患者炎症指标（CRP、MRI-SPINE）显着相关。因此，LIF可能通过促进成骨分化在AS的发病机制中发挥关键作用。
Aim Ankylosing spondylitis (AS) is a chronic inflammatory disease. However, the key inflammatory cytokines disrupted in this disease are not well defined. In this study, we performed protein array and multiple protein quantification to investigate the differentially expressed cytokines in plasma between AS patients and healthy subjects. Method In the discovery cohort, 5 AS patients who never underwent biologic therapy and 5 gender- and age-matched healthy subjects were enrolled in the protein array analysis. Another 40 AS patients and 20 healthy participants were recruited in the validation stage. In addition, the messenger RNA and protein levels of osteogenesis-related genes were quantified in hFOB1.19 cells in an in vitro osteoblast model. Results Of the 318 cytokines found to be differentially expressed by protein array, leukemia inhibitor factor (LIF) was significantly increased in AS patients as compared to controls. The "signaling by interleukins" pathway was the most enriched pathway in AS patients, and "signaling by interleukins"-related cytokines, including LIF, interleukin (IL)-6, IL-23, and IL-31, were significantly differentially expressed in the validation stage. Additionally, we correlated the expression of LIF with C-reactive protein (CRP) and inflammation of magnetic resonance imaging lesions in the spine (MRI-SPINE) in AS patients. We further analyzed the effects of LIF in hFOB cells and found that LIF promoted the growth factor receptor-bound protein 2 / phospho-extracellular signal-regulated kinase / runt-related transcription factor 2 / alkaline phosphatase pathway at the protein level and activated several osteogenesis-related genes (RUNX2 and BGLAP). Conclusion LIF was increased in the plasma of AS patients as compared with healthy subjects and significantly correlated with inflammation indices (CRP and MRI-SPINE) in AS patients. Thus, LIF may play a critical role in the pathogenesis of AS via promoting osteogenic differentiation.