Carboxyaminotriazole: A bone savior in collagen-induced arthritis—Halting osteoclastogenesis via interleukin-1β downregulation

Abstract

Aims

Rheumatoid arthritis (RA), a prevalent autoimmune disease, features inflammation and bone erosion, correlating with osteoclast hyperactivation and enhanced responsiveness to inflammatory factors. Reducing osteoclast formation and inflammatory mediator expression might avert bone erosion in RA. Carboxyaminotriazole (CAI) holds potential for treating autoinflammatory disorders and impeding cancer-related bone metastases. Yet, its bone-protective role and mechanism remain elusive. This study targets to explore the impacts and underlying mechanisms of CAI in preventing bone erosion in RA.

Materials and methods

A collagen-induced arthritis (CIA) rat model was utilized to evaluate the anti-RA potential of CAI. CCK-8, TRAP staining, TRAP activity assay, pit formation assay, RT-qPCR, Western blotting, immunofluorescence, and ELISA, were conducted to assess the effects and potential mechanisms of CAI in the management of RA.

Key findings

CAI not only reduces inflammatory symptoms, but it also offers superior bone protection compared to methotrexate (MTX) and works synergistically with MTX, the preferred anchoring agent for the treatment of RA. In vitro studies show that CAI inhibits osteoclast differentiation and function, as well as the expression of specific genes, by inhibiting NF-κB/MAPK pathways and reducing IL-1β levels. The deletion of Il-1 and the application of IL-1β inhibitors suggest that CAI retards osteoclastogenesis through the downregulation of IL-1β.

Significance

CAI may have therapeutic value in treating RA-related bone erosion, likely due to its inhibition of overactive osteoclasts by suppressing the NF-κB/MAPK pathways and the subsequent expression of IL-1β.