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Objective To study the effects of Guizhi Shaoyao Zhimu Decoction on factors related to bone destruction and bone protection in rats with collagen-induced arthritis (CIA) based on osteoprotegerin (OPG)/receptor activator of NF-?B ligand (RANKL)/receptor activator of NF-?B (RANK) signaling pathway. Methods According to the body weight, 60 female Wistar rats were randomly divided into the following six groups: the normal group, the model group, the Triperygium wilfordii multiglucoside group (0.01 g/kg), the Guizhi Shaoyao Zhimu Decoction low-dose group (8.6 g/kg), the Guizhi Shaoyao Zhimu Decoction medium-dose group (17.2 g/kg), and the Guizhi Shaoyao Zhimu Decoction high-dose group (34.4 g/kg) (n=10 rats per group). The rats in all groups except for the normal group were given 100 µg bovine type II collagen on the 1st and 8th days to establish the CIA model, and was injected into the left foot sole and tail root of the rats. After the successful modeling, the rats were treated by gavage for 4 weeks. The general state, body weight, and arthritis index (AI) score of rats were recorded, and the contents of RANKL and OPG in rat serum were determined by enzyme-linked immunosorbent assay. The mRNA and protein expressions of RANKL, RANK, and OPG in the ankle joint were determined through real-time PCR and Western blotting, respectively. Results Compared with the normal group, the general state of the model group was poor, the toe swelling was obvious, the AI score was increased, the serum RANKL content was increased, the serum OPG content was decreased, and the mRNA and protein expressions of RANKL and RANK in the ankle joint were increased (P<0.05). Compared with the model group, the degree of toe swelling and the AI score of rats in the Guizhi Shaoyao Zhimu Decoction low-, medium-, and high-dose groups were decreased, the serum RANKL content was decreased, the serum OPG content was increased, the mRNA and protein expressions of RANKL and RANK in the ankle joint were decreased, the mRNA and protein expressions of OPG were increased, and the RANKL/OPG ratio of the ankle joint was decreased(P<0.05). Conclusion Guizhi Shaoyao Zhimu Decoction can improve the destruction of joint bone in CIA rats, and its mechanism of action may be related to reducing RANKL level, reducing RANKL/OPG ratio, and regulating bone balance. [ABSTRACT FROM AUTHOR]