The phenotype we observe in limbs of Bmp2C/C; Bmp4C/C; Prx1::cre mice is similar to the phenotype reported for osterix knockout mice [46], which exhibited severe defects in osteoblastic differentiation. Since we observe fibroblastic cells adjacent to mineralized cartilage that have characteristics of osteoprogenitor cells but fail to express osterix in the absence of both BMP2 and BMP4, one important role of BMP2 and BMP4 during endochondral ossification may be to induce osterix gene expression in osteoprogenitors. Strikingly, however, we do observe osterix expression in the bone collar of E16.5 mice missing functional copies of both the Bmp2 and Bmp4 genes (K. Tsuji and A. Bandyopadhyay, unpublished data). This suggests that varying levels of expression from different BMP genes during preaxial and postaxial development result in fluctuations in total levels of BMP signaling, which at distinct times are above or below the threshold for supporting osteogenesis. While many osteogenic BMP molecules, apart from BMP2 and BMP4, such as BMP5, BMP6, and BMP7, are expressed during the endochondral process, our data suggest that these BMP molecules cannot compensate for the combined loss of BMP2 and BMP4 in bone formation. Recent biochemical and genetic experiments have suggested that individual BMPs have identical functions. BMP2, BMP4, BMP5, BMP6, and BMP7 can utilize the same type I (Alk2, Alk3, and Alk6) and type II receptors (BMP RII, ActRII, and ActRIIb) [47]. Once the complex between ligand and receptors is formed, BMP2, BMP4, BMP5, BMP6, and BMP7 direct the phosphorylation of the same set of BMP receptor–specific Smads (1, 5, or 8), and the signal that is transduced by each BMP appears to be identical in the skeletal target cells [48–51]. BMPs have also been shown to activate MAPK and AKT pathways and, based on current published information, each of the osteogenic BMPs appears to have the same capacity to activate these signaling pathways [52–54]. When this information is considered along with our observation that one allele of either Bmp2 or Bmp4 can rescue the osteoblast differentiation phenotype observed in Bmp2C/C; Bmp4C/C; Prx1::cre mice (see Figures 1I, 1J, 1Q, and 1R and S4), we favor the hypothesis that bone formation requires a threshold amount of BMP signaling which is not met when both BMP2 and BMP4 are completely absent. We cannot, however, exclude the possibility that BMP2 and BMP4 have distinct functions in osteoblastogenesis. Our analysis of skeletogenesis indicates that BMP2 and BMP4 are prerequisite for osteoblastogenesis while less important for chondrogenesis. These studies provide the first evidence linking BMP2 and BMP4 with bone formation in an in vivo setting where the preceding events of chondrogenesis are not compromised.