Although both TGF-beta and BMP signaling enhance expression of adhesion molecules during chondrogenesis. TGF-beta but not BMP signaling can initiate condensation of uncondensed mesenchymal cells. However, it remains unclear what causes the differential effects between TGF-beta and BMP signaling on prechondrogenic condensation. Our previous report demonstrated that ATP oscillations play a critical role in prechondrogenic condensation. Thus, the current study examined whether ATP oscillations are associated with the differential actions of TGF-beta and BMP signaling on prechondrogenic condensation. The result revealed that while both TGF-beta 1 and BMP2 stimulated chondrogenic differentiation, TGF-beta 1 but not BMP2 induced prechondrogenic condensation. It was also found that TGF-beta 1 but not BMP2 induced ATP oscillations and inhibition of TGF-beta but not BMP signaling prevented insulin-induced ATP oscillations. Moreover, blockage of ATP oscillations inhibited TGF-beta 1-induced prechondrogenic condensation. In addition, TGF-beta 1-driven ATP oscillations and prechondrogenic condensation depended on Ca2+ influx via voltage-dependent calcium channels. This study suggests that Ca2+-driven ATP oscillations mediate TGF-beta-induced the initiation step of prechondrogenic condensation and determine the differential effects between TGF-beta and BMP signaling on chondrogenesis. (C) 2012 Elsevier Inc. All rights reserved.