Bone defect arising secondary to trauma and cancer remains a major challenge for surgeons. Currently，mesenchymal stem cells are showed to be potential in its role in bone regeneration at clinical practice. The critical researches on the fate of stem cells in bone microenvironment as well as the interaction between them are still in the exploratory stage，which limits the development of stem cell⁃based therapies. Proteoglycans，the essential components and regulatory factors of the mesenchymal stem cell microenvironment，involve in the regulation of stem cell homestasis and osteogenic differentiation. Growing evidence has demonstrated that proteoglycans play a key role in regulating the regeneration of bone defects. Therefore，the domestic and foreign researches are now focusing on further revealing the mechanisms of proteoglycans in regulating the osteogenic differentiation of mesen⁃ chymal stem cells，and gradually promoting its topical application in the bone reconstruction field. This article has reviewed and summarized the latest research on the role of proteoglycans in regulating the osteogenic differentiation of different mesenchymal stem cells，its underlying mechanism and its current clinical application.