Overexpression of heparan sulfate 6-O-sulfotransferase-2 enhances fibroblast growth factor-mediated chondrocyte growth and differentiation

In our previous study, we reported that heparan sulfate 6-O-sulfotransferase2 (HS6ST2) plays an important role in the cartilage of patients with osteoarthritis and Kashin-Beck disease and that it regulates aggrecan (Acan) metabolism and the viability of chondrocytes. However, its role in chondrocyte differentiation remains poorly understood. In the present study, we aimed to investigate the role of HS6ST2 in chondrocyte differentiation in vitro using mouse prechondrocytic cells. We found that the overexpression or silencing of HS6ST2 significantly enhanced or abrogated the effects of fibroblast growth factor (FGF)2 on chondrocyte growth, respectively. We found that the overexpression of HS6ST2 significantly induced the expression of Acan as well as the amount of total proteoglycans in the prechondrocytic cells in the presence of FGF2, whereas the silencing of HS6ST2 caused the opposite effect. Furthermore, the expresssion of FGF2induced sexdetermining region Ytype high mobility group box protein 9 (SOX9), a major transcription factor for chondrocyte proliferation and differentiation, was also enhanced or blocked by HS6ST2 overexpression or HS6ST2 knockdown, respectively. Additionally, Wnt/βcatenin signaling, which inhibited chondrocyte proliferation and differentiation, was suppressed by HS6ST2. Taken together, these data suggest that HS6ST2 plays an important role in regulating chondrocyte growth and differentiation by modulating FGF2 signaling, thus indicating that it may be a potential and valuable molecular target for the treatment of skeletal dysplasias, such as dwarfism.