Abstract: BACKGROUND: β-Caryophyllene has a variety of pharmacological activities such as antioxidant, anti-inflammatory and anti-apoptotic, which may have a better therapeutic effect on osteoarthritis.
OBJECTIVE: To investigate the effect and mechanism of β-caryophyllene on mouse osteoarthritis. 
METHODS: Forty C57BL/6J mice were randomly divided into sham group, model group, low-dose β-caryophyllene group and high-dose β-caryophyllene group, with 10 mice in each group. Hulth method was used to construct an osteoarthritis model in the latter three groups. Four weeks after modeling, 70 and 
140 mg/kg/d β-caryophyllene was intragastrically given in the low- and high-dose β-caryophyllene groups, respectively, and normal saline was given by gavage in the sham group and the model group, once a day, for 4 weeks. After administration, knee joint morphological changes were observed by hematoxylin-eosin staining, serum levels of inflammatory factors (tumor necrosis factor-α, interleukin-1β, interleukin-6, and interleukin-10) were detected by ELISA, and oxidative stress indexes (glutathione peroxidase, superoxide dismutase, and malondialdehyde) were detected by chemiluminescence. The expression levels of key proteins in the Sonic hedgehog (Shh)/glioma associated oncogene homolog 1 (Gli1) signaling pathway were detected by immunohistochemistry and western blot. 
RESULTS AND CONCLUSION: (1) Compared with the sham group, a large number of inflammatory cells infiltrated in the knee joint of mice in the model group, cartilage tissue was seriously damaged, serum levels of tumor necrosis factor-α, interleukin-1β, interleukin-6, interleukin-10 and malondialdehyde were significantly increased (P < 0.01), the activities of glutathione peroxidase and superoxide dismutase were significantly decreased (P < 0.01), and the relative expression levels of Shh and Gli1 in the knee joint were significantly increased (P < 0.01). (2) Compared with the model group, in the low- and high-dose β-caryophyllene groups, inflammatory cell infiltration in the mouse knee joint was decreased, cartilage tissue injury was alleviated, serum levels of tumor necrosis factor-α, interleukin-1β, interleukin-6 and malondialdehyde were significantly decreased (P < 0.05), the activities of glutathione peroxidase and superoxide dismutase were significantly increased (P < 0.01), and the expression levels of Shh and Gli1 in the knee joint were significantly decreased (P < 0.01). The above-mentioned improvements were more significant in the high-dose β-caryophyllene group than the low-dose β-caryophyllene group. To conclude, β-caryophyllene can improve osteoarthritis, and its mechanism may be related to reducing inflammation and oxidative stress damage by regulating the Shh/Gli1 signaling pathway. 

Key words: β-caryophyllene, osteoarthritis, sonic hedgehog, glioma associated oncogene homolog 1, signaling pathway, mouse, engineered tissue construction