| The Bone Morphogenetic Protein (BMP) subgroup of the Transforming Growth Factor β (TGFβ) superfamily was originally identified by the ability of some BMPs to induce ectopic bone formation. BMPs have now been implicated in a diverse range of processes including cell proliferation, differentiation, and apoptosis. These processes occur in a variety of different tissue types in addition to bone. Most studies have focused on the founding members of the BMP family (e.g. BMP2, BMP4, and BMP7). In order to broaden our understanding of the family, we investigated a distantly related member, BMP3. Originally purified from bovine bone as Osteogenin, BMP3 was thought to induce ectopic bone in a manner similar to BMP2/4. In order to circumvent the possibility that the ability of osteogenin to induce bone is due to the presence of trace amounts of other BMPs, we utilized a retroviral system to infect bone marrow stromal cells with the BMP3 cDNA. Unlike BMP2, BMP3 did not induce alkaline phosphatase activity. When BMP3 was combined with BMP2, it was found to inhibit the ability of BMP2 to induce alkaline phosphatase. BMP3 was also found to inhibit BMP2 induction of the BMP-responsive construct Msx2-Lux. Mice deficient in Bmp3 were generated and were found to be viable on a mixed outbred strain background. However, adult Bmp3 −/− mice, were discovered to have twice the trabecular bone mass of wild-type littermates. These data showed a function for BMP3 in determining bone density. The Bmp3 null allele was then moved onto inbred mouse strain backgrounds, where it was discovered to be lethal when homozygous, with mice dying 24 hours after birth due to lung hypoplasia. Finally, BMP3 was discovered to synergize with BMP2 in certain epithelial cell types, possibly through the stimulation of a TGFβ/activin pathway or perhaps, the BMP receptor, ALK2.; In summary, my studies have shown that BMP3 plays a role in both osteoblasts and in lung epithelial cell types. BMP3-mediated signaling in specific cell types is sensitive to the effects of modifier alleles, and that, depending on the cell type BMP3 has the previously undescribed ability to stimulate either a TGFβ/activin, or a BMP pathway. |
