Mechanistic Role of the IL-1β/c-Fos/NFATc1 Signaling Axis in Echinococcal Infection-Elicited Osteoclastogenesis and Pathological Osteolysis: A Prospective Controlled Trial

Abstract Background Effective therapies for devastating osteolysis in osseous echinococcosis remain elusive, necessitating mechanistic exploration. To elucidate the molecular mechanism by which echinococcal infection promotes osteoclast differentiation and activation via the IL-1β/c-Fos/NFATc1 signaling axis in the pathological osteolysis of osseous echinococcosis. Methods Retrospective RT‒qPCR analysis was used to quantify the mRNA expression of osteoclastogenesis-associated inflammatory factors (TNF-α, IL-1β, IL-6, and IL-8) in bone cyst tissues from 21 osseous echinococcosis patients versus histologically normal bone adjacent to tumors in 21 matched bone tumor controls. Murine RAW 264.7 monocytes/macrophages were divided into the following groups: (i) Untreated control; (ii) Osteoclast induction (100 ng/mL RANKL + 25 ng/mL M-CSF); (iii-v) induction + hydatid antigen B (25/50/75 ng/mL); and (vi) induction + antigen B (75 ng/mL) + an IL-1β antagonist (canakinumab, 10 ng/mL). TRAP staining revealed osteoclasts (≥3 nuclei), with the percentage of positive cells calculated across ≥5 random fields. ELISA was used to measure cytokine levels in the supernatants; Western blotting was used to quantify c-Fos, NFATc1, cathepsin K, and MMP9 expression. The results Compared with control tissues, bone cyst tissues presented elevated TNF-α, IL-1β, IL-6, and IL-8 mRNA levels (P < 0.05). Antigen B (25–75 ng/mL) dose-dependently increased the number of TRAP⁺ cells and the levels of inflammatory cytokines compared with those in the induction group (P < 0.05). c-Fos, NFATc1, Cathepsin K, and MMP9 were upregulated in the induction and antigen B (75 ng/mL) groups compared with the control group (P < 0.05), with further elevation in the antigen B (75 ng/mL) group compared with the induction group (P < 0.05). Compared with antigen B (75 ng/mL), canakinumab reversed these protein increases (P < 0.05). Conclusion Echinococcal infection promotes pathological osteoclastogenesis and osteolysis through IL-1β/c-Fos/NFATc1 signaling activation.