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Objective The growth factor progranulin (PGRN) is widely expressed and plays important roles in anti-inflammatory signaling and bone regeneration. However, the anti-inflammatory and pro-osteogenic roles of PGRN in periodontitis are seldom studied. We used an in vitro model to investigate whether PGRN can promote osteogenic differentiation of periodontal ligament stem cells (PDLSCs). Methods PDLSCs were treated with PGRN (0 to 100 ng/mL) and the optimal concentrations required to induce proliferation and osteogenesis were identified. PDLSCs were cultured with 10 ng/mL tumor necrosis factor (TNF)-α, 25 ng/mL PGRN, or 10 ng/mL TNF-α + 25 ng/ml PGRN; untreated PDLSCs were used as controls. The effects of PGRN on PDLSC proliferation and osteogenic differentiation were assessed. Results PGRN (5, 25, and 50 ng/mL) promoted PDLSC proliferation and osteogenic differentiation, with the 25-ng/mL dose showing the largest effect. Furthermore, 25 ng/mL PGRN reversed inhibition of osteogenic differentiation by TNF-α. Conclusion PGRN promotes PDLSC proliferation, osteogenic differentiation, and mineralization in both inflammatory and non-inflammatory conditions. The 25-ng/mL PRGN dose was the most suitable for inducing proliferation and osteogenesis. Further studies using animal models will be required to obtain pre-clinical evidence to support using PGRN as a treatment for periodontitis.