About Bone Morphogenetic Proteins
BMP is the generic name of a family of proteins, identified originally in extracts of demineralized bone that were capable of inducing bone formation at ectopic sites. BMPs are found in minute amounts in bone material (approximately 1 microgram/kg dry weight of bone). In general the name BMP only describes one particular function of these proteins, which have been implicated also in various other processes. For some components of extracellular pathways that regulate the activity of bone morphogenetic protein see also: BMPER, Chordin, Crossveinless-2, Ectodin, TWSG1, KCP.
Some BMPs, including BMP2, BMP4, and BMP7, also play a role in the specification of hematopoietic tissue from the mesodermal germ layer. They regulate the proliferation and differentiation of highly purified primitive human hematopoietic cells (CD34(+), CD38(-), lin(-)) from adult and neonatal sources. Treatment of isolated stem cell populations with soluble BMP2, BMP4, and BMP7 induced dose-dependent changes in proliferation, clonogenicity, cell surface phenotype, and multilineage repopulation capacity after transplantation in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Some of the effects are concentration-dependent, with high concentrations of factors inhibiting proliferation and low concentrations inducing proliferation and differentiation (Bhatia et al, 1999).
With the exception of BMP1 members of the family of bone morphogenetic proteins (see also: gene family) belong to the TGF-beta superfamily of proteins. Among different morphogenetic proteins there is a considerable species conservation with a variety of proteins even being identical in several species. Many factors are synthesized with a signal sequence and as larger proproteins from which the mature proteins are derived. The BMP family comprises:
BMP1 (730 amino acids, incl. 22 amino acids encoding a signal sequence). The protein is not a member of the TGF-beta superfamily of proteins but is related to BP10 and is an alternatively spliced transcript of Mammalian tolloid. The protein is a cysteine-rich zinc-peptidase (see also: metalloproteinases) containing a CUB domain. The enzyme cleaves several pro-collagens into fragments that form mature collagen fibrils. It is identical with procollagen C-proteinase (EC220.127.116.11), a metalloproteinase involved in extracellular matrix (ECM) formation.
BMP2A (BMP2-alpha) This factor of 114 amino acids has been renamed BMP2. Human, mouse and rat proteins are identical in their amino acid sequences. The protein shows 68 % homology with Drosophila melanogaster dpp.
BMP2B (BMP2-beta; 116 amino acids) This factor has been renamed BMP4. Mouse and rat proteins are identical in their protein sequences.
BMP3 (110 amino acids) is a glycoprotein that is identical with Osteogenin. Human and rat mature proteins are 98 % identical. For a closely related factor from Xenopus laevis see: ADMP.
BMP3b (110 amino acids) is related to BMP3 (82 % identity). Human and mouse proteins show 97 % identity (3 different amino acids). Human and rat protein sequences differ by two amino acids. The factor is identical with GDF10.
BMP4 is identical with BMP2B and with DVR-4. It has been identified independently as BIP [bone-inducing protein] The protein shows 72 % homology with Drosophila melanogaster dpp. BMP4 has been shown to bind to noggin and chordin.
BMP5 is a protein of 138 amino acids. At the amino acid level human and mouse proteins are 96 % identical. In the mouse, mutations in the gene encoding BMP5 have been identified as the short ear locus.
BMP6 (139 amino acids) is identical with DVR-6 and vegetal-specific-related-1 (see also: Vg-1). It has been observed that approximately half of the BMP6 precursor (513 amino acids) remains uncleaved in the mouse before it is secreted. Meynard et al (2009) have reported that BMP6 is critical for iron homeostasis. Knock-out mice lacking expression of BMP6 show a rapid and massive accumulation of iron in the liver, the acinar cells of the exocrine pancreas, the heart, and the renal convoluted tubules. Hepcidin synthesis is markedly reduced. These mice retain their capacity to induce hepcidin in response to inflammation. The iron burden in BMP6 mutant mice is significantly greater than that in mice deficient in the gene associated with classical hemochromatosis (HFE), suggesting that mutations in BMP6 might cause iron overload in humans with severe juvenile hemochromatosis for which the genetic basis has not yet been characterized.
BMP7 (139 amino acids) is identical with OP-1 (osteogenic protein-1; see also: Vg-1). Mouse and human proteins are 98 % identical. The mature forms of BMP5, BMP6, and BMP7 show 75 % identity. See also: Eptotermin alfa.
BMP8 (139 amino acids) is identical with OP-2 (osteogenic protein-2). The factor is referred to also as BMP8a.
BMP8b (139 amino acids) is identical with OP-3 and has been found in mice only. The factor is known also as OP-3
BMP9 (110 amino acids) is referred to as GDF2 [growth/differentiation factor-2] also. BMP9 may act as a potential autocrine and paracrine mediator in the hepatic reticuloendothelial system.
BMP10 (108 amino acids) has been isolated from bovine sources. Bovine and human proteins are identical. Murine BMP10 expression has been shown to be restricted to the developing heart. It may play a role in trabeculation of the embryonic heart.
BMP11 (109 amino acids) has been isolated from bovine sources. Human and bovine sequences are identical. The protein is referred to also as GDF11.
BMP12 (104 amino acids). The factor is known also as GDF7 or CDMP-3.
BMP13 (120 amino acids) is the same as GDF6 and CDMP-2.
BMP14 (120 amino acids) is the same as GDF5 (approved gene symbol), CDMP-1, and LAP4.
BMP15 (125 amino acids) has been identified by Dube et al (1998) in the mouse and in humans. The gene maps to the X-chromosome in both species. The murine gene is expressed specifically in the oocyte. The murine protein is most closely related to murine GDF9 and is known also as GDF9B. Deletion of BMP15 results in reduced female fertility with the primary defects in ovulation and fertilization (Yan et al, 2001). Genetic targeting or spontaneous mutations of either GDF9 or BMP15 in mammals affect fertility in females (Juengel and McNatty, 2005).
Some of these proteins exist as heterodimers. OP-1, for example, associates with BMP2A.
BMP1 probably is a Zinc-containing metalloproteinase. BMP1 is considered a homolog of Astacin, a protease isolated from crayfish (Astacidae).
The other proteins of the BMP family are members of the transforming growth factor protein family (see: TGF-beta; Gene family). This is based on primary amino acid sequence homologies, including the absolute conservation of seven cysteine residues between TGF-beta and different BMPs.
From a high degree of amino acid sequence homology (approximately 90 %), BMP5, BMP6, and BMP7 are recognized as a distinct subfamily of the BMPs. Sequence analysis suggests that the Drosophila melanogaster 60A and members of this BMP subfamily are homologous. For novel members of the BMP family see also: CDMP (Cartilage-derived morphogenetic protein).
The human genes encoding BMP1, BMP2A and BMP3 map to chromosomes 8, 20p12, and 4p13-q21, respectively. They lie in the vicinity of the genes involved in the formation of cartilage and bone tissues. The genes encoding BMP5 and BMP6 map to human chromosome 6. The gene encoding BMP7 maps to human chromosome 20. In the mouse the BMP2A gene is located close to the Tsk (tight skin) locus, and it has been suggested that this gene may be the site for this mutation.
BMPs can be isolated from demineralized bones and osteosarcoma cells. They have been shown also to be expressed in a variety of epithelial and mesenchymal tissues in the embryo. Some BMPs (for example, BMP2 and BMP4) have been shown to elicit qualitatively identical effects (cartilage and bone formation) and to have the ability to substitute for one another.
BMPs are proteins that act to induce the differentiation of mesenchymal-type cells into chondrocytes and osteoblasts before initiating bone formation. They promote the differentiation of cartilage-forming cells and bone-forming cells near sites of fractures but also at ectopic locations. Some of the proteins induce the synthesis of alkaline phosphatase and collagen in osteoblasts. Some BMPs act directly on osteoblasts and promote their maturation while at the same time suppressing myogenous differentiation. Other BMPs promote the conversion of typical fibroblasts into chondrocytes and are capable also of inducing the expression of an osteoblast phenotype in non-osteogenic cell types. Intracellular signaling following engagement of receptors for some BMP proteins has been shown to involve the action of SMAD proteins.
In addition, some BMPs and also some related factors may be involved in embryonic development. Osteogenin and related BMPs also promote additional successive steps in the endochondral bone formation cascade by functioning as potent chemoattractants (see also: Chemotaxis) for circulating monocytes and by inducing, among other things, the synthesis and secretion of TGF-beta-1 (see: TGF-beta) by monocytes. Monocytes stimulated by TGF-beta secrete a number of chemotactic (see also: Chemotaxis) and mitogenic cytokines into the conditioned medium that recruit endothelial and mesenchymal cells and promote the synthesis of collagen and associated matrix constituents.
Limb development and outgrowth depends on epithelial-mesenchymal interactions. It is regulated by a combination of stimulatory and inhibitory signals secreted by the apical ectodermal ridge, a specialized epithelium at the limb tip, responsible for the stimulation of proliferation of the underlying mesenchyme. Proliferation of mesenchyme in the early mouse limb-bud is stimulated by FGF-4 produced by the apical ectodermal ridge, and BMP2 has been shown to inhibit limb growth.
It has been shown that mutations at the classic mouse locus short ear (se) on chromosome 9, associated with a specific spectrum of morphologic alterations in the ear and many internal skeletal structures, disrupt the mouse homolog of the BMP5 gene. The mutant animals also have a defect in bone fracture repair and show soft tissue abnormalities including lung cysts, liver granulomas, and hydrotic kidneys.
The activity of BMPs is antagonized in vivo and in vitro by a factor called OIP (osteogenesis inhibitory protein) while some activities of BMPs may be enhanced by Activin A or TGF-beta.
BMP4 and BMP7 have been shown to be involved also in the differentiation of sympathetic neurons. They enhance the formation of adrenergic sympathetic neurons in cultures of neural crest cells. The same activity is seen in the developing embryo in vivo following ectopic expression of the two factors. Factors isolated initially from Xenopus laevis and subsequently also from other sources appear to behave as BMP antagonists (see: Gremlin, Cerberus, noggin, chordin, DAN).
The product of the DAF4 gene from Caenorhabditis elegans has been shown to be a receptor for BMP. Another receptor, designated BRK-1, which binds BMP2 and BMP4, has been isolated from mouse embryonic NIH 3T3 fibroblasts. BRK-1 (64 kDa) is a member of the transmembrane serine/threonine kinase family resembling most closely the cloned type 1 receptors for TGF-beta and Activin A. Complex formation between BRK-1 and DAF4 can be demonstrated when the two receptors are coexpressed.