The TNF-NF-κB-DKK1 Axis Promoted Bone Formation in the Enthesis of Ankylosing Spondylitis

Objective. This study aimed to determine the serum Dickkopf 1 (DKK1) levels in ankylosing spondylitis (AS) patients and decipher the mechanism of tumor necrosis factor (TNF)-mediated DKK1 regulation in human AS enthesis cells. Methods. The sera were obtained from 103 patients with AS and 30 healthy controls (HCs). The enthesis of facet joints were obtained from 4 AS patients and 5 controls. The serum levels of DKK1 were measured using ELISA and compared between AS and HCs. The impact of TNF on DKK1 expression in human primary spinal enthesis cells was evaluated using various molecular biology techniques and bone formation indicators. Results. AS patients showed higher serum DKK1 levels than HCs after adjusting for age (917.4 [615.3 similar to 1,310.0] pg/mL vs. 826.2 [670.3 similar to 927.8] pg/mL, p = 0.043). TNF treatment promoted bone formation and DKK1 expression in both control enthesis cells and those of AS. This enhanced bone formation by TNF was pronounced in AS-enthesis than those of controls. Mechanically, TNF induced NF-kappa B activation upregulates the DKK1 transcript level. While, NF-kappa B inhibitor led to downregulate DKK1 expression in the enthesis. Besides, DKK1 overexpression promoted bone formation in enthesis. Conclusion. TNF induced DKK1 expression in the enthesis through NF-kappa B activation. TNF-induced DKK1 expression may play a bone formation in the radiologic progression of ankylosing spondylitis.

Automated summary

This study found that AS patients have higher serum DKK1 levels compared to healthy controls, and TNF treatment can promote bone formation and DKK1 expression in enthesis cells. TNF-induced NF-kappa B activation upregulates DKK1 transcription, leading to enhanced bone formation in AS patients. Overall, DKK1 expression induced by TNF may contribute to the bone formation seen in the progression of ankylosing spondylitis.