Objective <p>Osteoarthritis (OA) is closely related to aging, and autophagy is implicated in the retardation of aging. Activated synoviocytes play important roles in OA; the synoviocytes could produce osteopontin (OPN) and its main receptors CD44 and integrin, which are all involved in OA. The purpose of this study is to investigate whether OPN has an effect on autophagy in osteoarthritic synoviocytes.</p> Methods <p>We cultured human OA fibroblast-like synoviocytes (FLS) and treated them with rhOPN and antibodies against CD44 and CD51/61 (αvβ3 integrin) or isotype IgG to block the interaction between receptors and ligands. Infection with lentivirus mRFP-GFP-LC3, laser confocal imaging and Western blotting were used to determine changes in the expression of autophagy markers, and cell proliferation of FLS was assessed with a CCK-8 assay.</p> Results <p>Our results showed the expression level of autophagy marker protein LC3 II and the mRFP-GFP-LC3 puncta were significantly decreased after treatment with rhOPN when compared with the control group, when the FLS were incubated with antibodies against CD44 or CD51/61 (αvβ3 integrin) or with control isotype IgG for 1&#xa0;h, followed by rhOPN treatment for 48&#xa0;h, rhOPN could suppress the relative expression of LC3 II and Beclin1 via integrin and CD44 in the FLS, CCK-8 assay also showed that rhOPN significantly increased the cell proliferation and viability of FLS.</p> Conclusions <p>OPN could inhibit autophagy via CD44 and αvβ3 integrin and promote the proliferation of FLS, playing an important role in OA synovitis.</p>