Heparan sulfate (HS) proteoglycan is a widely distributed biological molecule that mediates a variety of physiological responses in development, cell growth, cell migration, and wound healing. We examined the effects of basic fibroblast growth factor-2 (FGF-2), which is known to modulate extracellular matrix (ECM) production of various cell types, on the production of HS proteoglycan by human periodontal ligament (HPDL) cells. We also examined the effects of FGF-2 on the expression of syndecans, a major family of membrane-bound HS proteoglycans. Treatment of HPDL cells with FGF-2 for 72 h resulted in a pronounced increase in the level of HS in the culture supernatant in a dose-dependent manner. However, reverse transcription-polymerase chain reaction data (RT-PCR) revealed that FGF-2 marginally reduced the gene expression of syndecan-1, -2, and -4, and did not alter the level of syndecan-3 mRNA. Furthermore, FGF-2 did not have an effect on the mRNA expression of enzymes associated with HS biosynthesis. Interestingly, FACS analysis revealed that the syndecan family displayed diverse alterations in response to FGF-2. FGF-2 barely altered the expression of syndecan-1, but decreased the expression of syndecan-2 and -4 on HPDL cells. Moreover, dot blot analysis showed that FGF-2 did not alter the level of syndecan-1 and -2, but enhanced the level of syndecan-4 in culture supernatants of FGF-2-stimulated HPDL cells. These results suggest that the FGF-2-activated increase in the level of HS in conditioned medium may be a result of shedding of syndecan-4 from the HPDL cell surface. Taken together, FGF-2 may differentially regulate the expression of HS proteoglycans in a HS-proteoglycan-subtype-dependent manner. The diversity of the expression patterns of HS proteoglycans may be associated with the FGF-2-induced biological functions of HPDL cells.