Leukemia inhibitory factor is dysregulated in ankylosing spondylitis and contributes to bone formation

Abstract

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.

Risk of Ankylosing Spondylitis in Patients With Endometriosis: A Population-Based Retrospective Cohort Study

“…For endometriosis, the vigorous inflammatory response will cause endometrial cells to release more chemokines, namely, IL-1β, IL-6, IL-8, TNF-α, and IL-17 ( 10 , 11 ). Also, increased levels of IL-6, TNF-α, IL-1β, and IL-17 could be detected in AS patients ( 12 , 14 , 15 ). Moreover, both TNF-α and IL-17 inhibitors have therapeutic effects on AS ( 16 , 17 ).…”

Differentially expressed protein‐coding genes in ankylosing spondylitis: Emerging insights into pathogenesis and therapeutic approaches

“…Leukemia inhibitory factor (LIF) has been demonstrated to be higher in the plasma of patients with AS compared with health controls, and it is substantially linked with inflammation markers in these patients. As a result, by encouraging osteogenic differentiation, LIF may be essential in the pathogenesis of AS 130 . Platelet‐derived growth factor‐β receptor (PDGFRB) was discovered to be increased during fibroblast osteogenesis and enhances osteogenesis in AS.…”

“…As a result, by encouraging osteogenic differentiation, LIF may be essential in the pathogenesis of AS. 130 Platelet-derived growth factorβ receptor (PDGFRB) was discovered to be increased during fibroblast osteogenesis and enhances osteogenesis in AS. In comparison to controls, the expression of PDGFRB was considerably higher in the facet and spinous enthesis joints of AS.…”

miR-30a inhibits the osteogenic differentiation of the tibia-derived MSCs in congenital pseudarthrosis via targeting HOXD8

“…Runx2 plays a vital role in osteogenic differentiation [ 31 , 32 ]. For instance, blocking the NLRP3 inflammasome could reduce osteogenic differentiation via inhibition of RUNX2 [ 33 ].…”