Interleukin-33 drives abnormal bone remodeling in ankylosing spondylitis via inhibition of osteoclast differentiation.

OBJECTIVES

Interleukin (IL)-33 has been shown to be abnormally expressed in patients diagnosed with ankylosing spondylitis (AS). However, the source of IL-33 and the mechanism(s) through which IL-33 affects bone metabolism in AS remains unclear.

METHODS

Serum IL-33 levels were measured in patients diagnosed with AS and healthy controls (HCs). Primary human enthesis cells were isolated from surgically harvested human enthesis tissues to evaluate IL-33 expression under tumor necrosis factor (TNF) and IL-17A stimulation using bulk RNA sequencing and Western blotting. The therapeutic potential of IL-33 in curdlan-treated SKG mice to mimic AS was assessed using anti-IL-33 neutralizing antibodies. The effects of IL-33 on bone remodeling were further explored using osteoblast and osteoclast differentiation assays.

RESULTS

Serum IL-33 levels were significantly elevated in patients with AS with a high inflammatory burden and were positively correlated with TNF, IL-17A, and radiographic progression. In AS enthesis tissues and primary cells, IL-33 expression was markedly higher than that in HCs. Notably, synergistic stimulation by TNF and IL-17A significantly upregulated IL-33 at both the transcriptomic and protein levels, particularly in ASenthesis cells. In vivo, anti-IL-33 treatment significantly attenuated clinical arthritis severity, enthesitis scores, and enthesophyte formation in a mouse model of AS. Mechanistically, IL-33 significantly inhibited osteoclastogenesis by suppressing the p38 MAPK-NFATc1 signaling pathway in osteoclast precursors.

CONCLUSION

These findings demonstrate that IL-33 is a key mediator that links systemic inflammation to local enthesopathy and pathological bone formation in patients with AS. Accordingly, the IL-33/p38/NFATc1 axis may offer a crucial mechanistic link between osteoclasts and osteoblasts for understanding the pathological bone remodeling characteristics of AS.