Chondrocyte degeneration and extracellular matrix component loss are the primary causes of osteoarthritis (OA). OA can be treated by inhibiting chondrocyte degeneration and increasing extracellular matrix component secretion. Osteopontin (OPN)

a multifunctional protein

has gained immense attention with regard to its involvement in OA. This study aimed to explore the therapeutic value and mechanism of action of OPN in OA treatment. Results of the histomorphological analysis revealed a worn-off OA cartilage tissue surface

cartilage matrix layer deterioration

and calcium salt deposition. Compared to that in normal chondrocytes

in OA chondrocytes

the OPN

CD44

and PI3K protein and mRNA expression was upregulated. Further

siOPN

rhOPN

and rhOPN plus LS-C179404 interfered with OA chondrocytes. As verified in mice

OPN directly inhibited the expression level of PI3K in OA chondrocytes by binding with CD44. Morphological analysis of the knee joints demonstrated that OPN effectively inhibited OA progression via the OPN/CD44/PI3K signal axis. In conclusion

OPN activates intracellular PI3K signaling molecules by binding to CD44 on the cell surface to cause downstream cascading effects

thereby delaying chondrocyte degeneration and reducing cartilage matrix component loss; therefore

OPN is a potential therapeutic agent for OA.