〔Abstract〕 Objective To investigate the effect of blocking the B7/CD28 pathway on rheumatoid arthritis mice and its possible mechanism. Methods 40 DBA/1 mice were randomly divided into normal control group, model group, CTLA4-Ig low-dose group and cytotoxic T lymphocyte antigen-4 immunolobulin(CTLA4-Ig) high-dose group. Except for the normal control group, the other three groups were prepared for rheumatoid arthritis models. At 0, 5 and 10 days after the second immunization, the CTLA4-Ig low-dose group and CTLA4-Ig high-dose group were intraperitoneally injected with 50 mg/kg and 100 mg/kg CTLA4-Ig, respectively, the normal control group and the model group were injected with the same amount of saline. Vernier calipers were used to measure the thickness of the ipsilateral hindfoot of the mouse for arthritis score; the serum levels of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), interleukin-6(IL-6) and interleukin-17(IL-17) were detected by ELISA, images were acquired and bone tissue morphometric parameters were measured through Micro-CT scanning, HE staining observed the pathological changes of the knee joint, TRAP staining detected osteoclasts in knee joint tissues, real-time fluorescent quantitative PCR and Western blot detected osteoprotegerin(OPG), receptor activator of NF-κB(RANK), receptor activator of NF-κB ligand(RANKL) mRNA and protein expression, immunohistochemical staining detected nuclear factor κB(NF-κB) expression. Western blot was used to detect the expression of related proteins in the NF-κB signaling pathway. Results Compared with the model group, after high-dose CTLA4-Ig treatment, RA mouse foot swelling and arthritis scores were reduced, the levels of TNF-α, IL-1β, IL-6 and IL-17 in serum were reduced, the knee joint damage was significantly reduced, bone mineral density(BMD), trabecular thickness(Tb.Th), bonevolume(BV) and bone volume fraction(BV/TV) increased, the number of TRAP positive cells decreased, the relative expression of OPG mRNA and protein in the tissue was up-regulated, while the relative expression of RANK, RANKL mRNA and protein were down-regulated. At the same time, the relative expression of p-p65 and p-IκBα protein decreased, the positive expression area of NF-κB decreased, and the difference were statistically significant(P<0.01); After CTLA4-Ig low-dose treatment, the serum levels of TNF-α, IL-1β, IL-6 and IL-17 in RA mice were significantly lower than those in the model group, and the area of NF-κB positive expression in the tissue was reduced, the difference were statistically significant(P<0.01). Conclusion CTLA4-Ig to block the B7/CD28 pathway has a significant therapeutic effect on mouse rheumatoid arthritis, which can inhibit the inflammatory response, reduce bone destruction and prevent the activation of the NF-κB signaling pathway.