After reduction, the highly purified BMP fraction at approximately 30 kDa was
found to consist of several peptides, suggesting that BMP is not a single protein [10], [14], [15] and [16]. Indeed, amino acid selleck chemical sequences of the peptides indicate the presence of distinct but related molecules, including BMP-1, BMP-2/BMP-2A, BMP-3/osteogenin, BMP-4/BMP-2B, BMP-5, BMP-6/Vgr-1 and BMP-7/OP-1 [10], [15], [16] and [17]. Among these compounds, only BMP-1 has a distinct structure and belongs to the metalloproteinase family [14]. The other BMPs are related to each other and can be classified into multiple subclasses of the transforming growth factor-β (TGF-β) family, which contains several other members in both vertebrate and invertebrate species [14], [15], [17] and [18]. Importantly, each of the recombinant proteins, including BMP-2, BMP-4 and BMP-7, has been shown to induce heterotopic bone formation in vivo, confirming the presence of original “BMP” activity [14], [19] and [20]. It was also shown that the bone-inducing activity of the extracts of demineralized bone and dentin could be attributed to several BMPs. Two recombinant Drosophila BMP homologs, Dpp and 60A, also induced heterotopic bone formation in rodents, suggesting that the signal transduction mechanisms
are conserved across vertebrate and invertebrate species [21] and [22]. To date, genes encoding more than 20 members of the BMP and related growth and differentiation factor (GDF) families have been found in the human genome. Several Alectinib solubility dmso BMPs and GDFs Montelukast Sodium have been shown to induce the formation of bone and/or cartilage tissue not only through the implantation of recombinant proteins but also through the transduction of individual cDNAs into sites in vivo using viral vectors or the implantation of cell transduced viral vectors [23] and [24]. TGF-β1 and
TGF-β2 were identified as cartilage-inducing factor-A (CIF-A) and CIF-B, respectively, in bone extracts in a chondrogenesis assay of muscle cells [13] and [25]. However, the implantation of TGF-β1 in vivo failed to induce heterotopic bone formation [26]. Interestingly, a combination of TGF-β1, TGF-β2 or activin with BMP-2 exhibited potent heterotopic bone-inducing activity in vivo [27], [28] and [29]. A small proteoglycan known as osteoglycin has also been shown to enhance the bone-inducing activity of BMP-2 [30] and [31]. The molecular mechanisms underlying the synergistic behavior of BMPs and other molecules remain unclear. Neither the functional receptors nor the downstream effectors of the TGF-β family had been identified when BMPs were first isolated from bone extracts. To examine the details of their intracellular signaling, various cell lines were screened for high responsiveness to BMP-2 in vitro.
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