Alternative titles; symbols
HGNC Approved Gene Symbol: BMP7
Cytogenetic location: 20q13.31 Genomic coordinates (GRCh38): 20:57,168,753-57,266,641 (from NCBI)
Bone morphogenetic protein-7 is a member of the transforming growth factor-beta (see TGFB1, 190180) superfamily of regulatory molecules. See 112265.
Ozkaynak et al. (1990) purified a novel bovine osteogenic protein homolog, which they termed 'osteogenic protein-1' (OP1). The authors used peptide sequences to clone the human genomic and cDNA clones of OP1, later named BMP7. The BMP7 cDNAs predicted a 431-amino acid polypeptide that includes a secretory signal sequence.
Using bovine Bmp6 (112266) to screen a U2-OS cell line cDNA library, followed by rescreening a primer-extended U2-OS cell line cDNA library, Celeste et al. (1990) cloned BMP7. The deduced full-length 431-amino acid protein contains a hydrophobic leader sequence followed by a proprotein region and a C-terminal mature domain with 3 potential N-glycosylation sites. Sequence comparison suggested that BMP2 (112261), BMP5 (112265), BMP6, and BMP7 form a BMP subfamily.
Marker et al. (1995) studied the distribution of BMP7 transcripts at various anatomic sites disrupted by Holt-Oram syndrome (142900) mutations. They found BMP7 expression in all structures that are altered in Holt-Oram patients, including the heart, proximal and distal forelimb, clavicle, and scapula, as well as other unaffected tissues.
Solursh et al. (1996) examined developmental and temporal expression of OP1 by hybridization with histologic sections of rat embryos during a 3-day period comprising the primitive streak stages to early limb bud stages. OP1 expression was detected in the neuroepithelium of the optic vesicle at day E11.5 and was limited to the presumptive neural retina and developing lens placode. From E12.5-E13.5, they found expression in the neural retina, lens, and developing cornea.
Hahn et al. (1992) mapped the BMP7 gene to human chromosome 20 by study of human-rodent somatic cell hybrid lines with cDNA probes. BMP2 (112261) also maps to chromosome 20. Marker et al. (1995) assigned mouse Bmp7 to distal chromosome 2 by interspecific backcross mapping. Marker et al. (1995) suggested that the human BMP7 gene may be on 20q13.1-q13.3, extrapolating from the fact that the Bmp7 gene in the mouse is between Ada (608958), localized to 20q12-q13.11, and Pck1 (261680), localized to 20q13.2-q13.31.
Gross (2015) mapped the BMP7 gene to chromosome 20q13.31 based on an alignment of the BMP7 sequence (GenBank AK291186) with the genomic sequence (GRCh38).
Beck et al. (2001) showed that recombinant human BMP5 and BMP7 independently elicited dendritic growth in cultured rat superior cervical neurons. Their effects were not additive.
You and Kruse (2002) studied corneal myofibroblast differentiation and signal transduction induced by the TGFB family members activin A (147290) and BMP7. They found that activin A induced phosphorylation of SMAD2 (601366), and BMP7 induced SMAD1 (601595), both of which were inhibited by follistatin (136470). Transfection with antisense SMAD2/SMAD3 (603109) prevented activin-induced expression and accumulation of alpha-smooth muscle actin. The authors concluded that TGFB proteins have different functions in the cornea. Activin A and TGFB1, but not BMP7, are regulators of keratocyte differentiation and might play a role during myofibroblast transdifferentiation. SMAD2/SMAD3 signal transduction appeared to be important in the regulation of muscle-specific genes.
Cheng et al. (2003) measured the ability of 14 human BMPs to induce osteogenic transformation in a mouse pluripotential stem cell line, a mouse mesenchymal stem cell line, and a mature human osteoblastic cell line. Osteogenic activity was determined by measuring the induction of alkaline phosphatase (see 171760), osteocalcin (112260), and matrix mineralization upon BMP stimulation. All BMPs except BMP3 (112263) and BMP12 (604651) were able to stimulate alkaline phosphatase activity in the mature osteoblasts. BMP7 was able to induce all markers of osteoblast differentiation in pluripotential and mesenchymal stem cells; however, BMP7 was a weaker inducer than BMP2, BMP6, and BMP9 (GDF2; 605120).
Commissural neurons extend their axons ventrally, away from the roof plate, during spinal cord development. The roof plate is the source of a diffusible repellent that orients commissural axons in vitro, suggesting it may regulate the trajectory of commissural axons in vivo. Of the 3 BMPs expressed in rodent roof plate, Bmp7, but not Bmp6 or Gdf7 (604651), mimics the repellent activity of the roof plate in vitro (Augsburger et al., 1999). Using roof plate tissue from mice lacking Bmp7, Bmp6, and Gdf7 alone or in paired combinations, Butler and Dodd (2003) showed that both Bmp7 and Gdf7 were required by roof plate cells for the fidelity of commissural axon growth in vivo. Bmp7 and Gdf7 heterodimerized in vitro, and Gdf7 enhanced the axon-orienting activity of Bmp7. Butler and Dodd (2003) concluded that a GDF7/BMP7 heterodimer functions as a roof plate-derived repellent that establishes the initial ventral trajectory of commissural axons.
In mesangial cells that regulate glomerular fibrosis, BMP7 inhibits TGFB-induced fibrogenesis, primarily by preventing TGFB-dependent downregulation of matrix degradation and upregulation of plasminogen activator inhibitor-1 (PAI1, or SERPINE1; 173360). Using murine mesangial cells in culture, Wang and Hirschberg (2004) found that application of recombinant human BMP7 reduced nuclear accumulation of Smad3 and blocked Tgfb/Smad3-dependent upregulation of a reporter gene for Caga (S100A8; 123885), a Smad3 target. Smad5 (603110) was the preferred BMP7-induced receptor-activated SMAD in mesangial cells. Knockdown of Smad5 in murine mesangial cells impaired the ability of BMP7 to interfere with Tgfb-dependent activation of the Caga reporter or with Tgfb-induced accumulation and secretion of Pai1. Knockdown of Smad5 also reduced BMP7-dependent upregulation of inhibitory Smad6 (602931). Wang and Hirschberg (2004) concluded that BMP7 opposes TGFB-dependent mesangial fibrosis in a manner that requires SMAD5 and that involves activation of inhibitory SMAD6 downstream of SMAD5 and a reduction in nuclear SMAD3.
Zeisberg et al. (2007) showed that cardiac fibrosis is associated with the emergence of fibroblasts originating from endothelial cells, suggesting an endothelial-mesenchymal transition (EndMT) similar to events that occur during formation of the atrioventricular cushion in the embryonic heart. TGFB1 induced endothelial cells to undergo EndMT, whereas BMP7 preserved the endothelial phenotype. The systemic administration of recombinant human BMP7 significantly inhibited EndMT and the progression of cardiac fibrosis in mouse models of pressure overload and chronic allograft rejection. Zeisberg et al. (2007) concluded that EndMT contributes to the progression of cardiac fibrosis and that recombinant human BMP7 can be used to inhibit EndMT and to intervene in the progression of chronic heart disease associated with fibrosis.
Using transgenic mice expressing various portions of the Bmp7 promoter, Adams et al. (2007) identified a regulatory island in intron 1 that governed expression of a reporter gene in developing iris, renal collecting duct, and limb mesenchyme. This regulatory element was highly conserved in humans and terrestrial vertebrates, but was absent in aquatic vertebrates. Selective deletions and site-directed mutagenesis within this element revealed a critical Foxd3 (611539)-binding site that was vital for expression of a Bmp7 reporter in limb, midbrain-hindbrain junction, and Wolffian duct.
Tseng et al. (2008) demonstrated that whereas some members of the BMP family support white adipocyte differentiation, BMP7 singularly promotes differentiation of brown preadipocytes even in the absence of the normally required hormonal induction cocktail. BMP7 activates a full program of brown adipogenesis, including induction of early regulators of brown fat fate PRDM16 (605557) and PGC1A, increased expression of the brown fat-defining marker uncoupling protein-1 (UCP1; 113730) and adipogenic transcription factors PPAR-gamma (601487) and CCAAT/enhancer-binding proteins (C/EBPs; see 116897), and induction of mitochondrial biogenesis via p38 mitogen-activated protein kinase (MAPK14; 600289), and PGC1-dependent pathways. Moreover, BMP7 triggers commitment of mesenchymal progenitor cells to a brown adipocyte lineage, and implantation of these cells into nude mice resulted in development of adipose tissue containing mostly brown adipocytes. Bmp7 knockout mouse embryos showed a marked paucity of brown fat and an almost complete absence of UCP1. Adenoviral-mediated expression of BMP7 in mice resulted in a significant increase in brown, but not white, fat mass and led to an increase in energy expenditure and a reduction in weight gain. Tseng et al. (2008) concluded that their data revealed an important role of BMP7 in promoting brown adipocyte differentiation and thermogenesis in vivo and in vitro, and provided a potential new therapeutic approach for the treatment of obesity.
By database analysis, Long et al. (2013) identified potential binding sites for microRNA-22 (MIR22; 612077) in the 3-prime UTRs of mouse Bmp6, Bmp7, and Bmpr1b (603248). Western blot analysis detected significant downregulation of Bmp6 and Bmp7 in mouse renal fibroblasts transfected with Mir22. Reporter gene assays and Mir22 pull-down experiments confirmed that the Bmp6, Bmp7, and Bmpr1b transcripts were Mir22 targets. In addition, the authors identified 3 potential BMP-responsive elements in the mouse Mir22 promoter region. Quantitative RT-PCR analysis showed increased MIR22 expression following treatment of human embryonic fibroblasts with BMP6, suggesting a negative-feedback loop.
Crystal Structure
Groppe et al. (2002) reported the crystal structure of the antagonist noggin (NOG; 602991) bound to BMP7, which showed that noggin inhibits BMP signaling by blocking the molecular interfaces of the binding epitopes for both type I and type II receptors. The BMP7 binding affinity of site-specific variants of noggin was correlated with alterations in bone formation and apoptosis in chick limb development, showing that noggin functions by sequestering its ligand in an inactive complex. The scaffold of noggin contains a cystine (the oxidized form of cysteine) knot topology similar to that of BMPs. Thus, Groppe et al. (2002) concluded that ligand and antagonist seem to have evolved from a common ancestral gene.
Dudley et al. (1995) found that Bmp7-null mice displayed severe defects confined to the kidney and eye. At midgestation and later, Bmp7-null embryos were readily identified by their severe ocular defects, which included bilateral anophthalmia, unilateral anophthalmia with unilateral microphthalmia, and bilateral microphthalmia. No other head structures were affected. Late-gestation mutants and live-born mutants exhibited severe bilateral renal dysplasia, often accompanied by massive hydroureter. Gonads and adrenal glands were unaffected. A proportion of Bmp7-null mutants displayed unilateral hindlimb polydactyly and failure of 1 or both of the seventh pair of ribs to fuse to the sternum. The vast majority of Bmp7-null mice died within the first day of life, probably due to renal failure, and none survived more than 10 days.
Jena et al. (1997) found that inactivation of Bmp7 in mice impaired development of the axial skeleton from skull to tail, caused holes in basisphenoid bone and xyphoid cartilage, and retarded ossification of bones, in addition to causing ocular and renal defects.
Fuller et al. (2007) found that Bmp4 (112262) and Bmp7 increased rapidly at the site of chemically-induced demyelinating lesions in adult rat spinal cord. The Bmp proteins stimulated Smad (see, e.g., SMAD1; 601595) activation in mature astrocytes, resulting in increased expression of chondroitin sulfate proteoglycans and glial scar formation.
Suzuki et al. (2008) showed that Dlx5 (600028), Dlx6 (600030), p63 (TP63; 603273), and Bmp7, a putative p63 target gene, were all expressed in developing mouse urethral plate. Targeted inactivation of p63, Bmp7, or both Dlx5 and Dlx6 resulted in abnormal urethra formation in mice.
Using conditional knockout mice, Kazama et al. (2008) found that lack of Bmp7 expression in glomerular podocytes impaired cellular proliferation in developing proximal tubules.
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Augsburger, A., Schuchardt, A., Hoskins, S., Dodd, J., Butler,P S. BMPs as mediators of roof plate repulsion of commissural neurons. Neuron 24: 127-141, 1999. [PubMed: 10677032] [Full Text: https://doi.org/10.1016/s0896-6273(00)80827-2]
Beck, H. N., Drahushuk, K., Jacoby, D. B., Higgins, D., Lein, P. J. Bone morphogenetic protein-5 (BMP-5) promotes dendritic growth in cultured sympathetic neurons. BMC Neurosci. 2: 12, 2001. Note: Electronic Article. [PubMed: 11580864] [Full Text: https://doi.org/10.1186/1471-2202-2-12]
Butler, S. J., Dodd, J. A role for BMP heterodimers in roof plate-mediated repulsion of commissural axons. Neuron 38: 389-401, 2003. [PubMed: 12741987] [Full Text: https://doi.org/10.1016/s0896-6273(03)00254-x]
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Fuller, M. L., DeChant, A. K., Rothstein, B., Caprariello, A., Wang, R., Hall, A. K., Miller, R. H. Bone morphogenetic proteins promote gliosis in demyelinating spinal cord lesions. Ann. Neurol. 62: 288-300, 2007. [PubMed: 17696121] [Full Text: https://doi.org/10.1002/ana.21179]
Groppe, J., Greenwald, J., Wiater, E., Rodriguez-Leon, J., Economides, A. N., Kwiatkowski, W., Affolter, M., Vale, W. W., Belmonte, J. C. I., Choe, S. Structural basis of BMP signalling inhibition by the cystine knot protein Noggin. Nature 420: 636-642, 2002. [PubMed: 12478285] [Full Text: https://doi.org/10.1038/nature01245]
Gross, M. B. Personal Communication. Baltimore, Md. 2/26/2015.
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Jena, N., Martin-Seisdedos, C., McCue, P., Croce, C. M. BMP7 null mutation in mice: developmental defects in skeleton, kidney, and eye. Exp. Cell Res. 230: 28-37, 1997. [PubMed: 9013703] [Full Text: https://doi.org/10.1006/excr.1996.3411]
Kazama, I., Mahoney, Z., Miner, J. H., Graf, D., Economides, A. N., Kreidberg, J. A. Podocyte-derived BMP7 is critical for nephron development. J. Am. Soc. Nephrol. 19: 2181-2191, 2008. [PubMed: 18923055] [Full Text: https://doi.org/10.1681/ASN.2007111212]
Long, J., Badal, S. S., Wang, Y., Chang, B. H. J., Rodriguez, A., Danesh, F. R. MicroRNA-22 is a master regulator of bone morphogenetic protein-7/6 homeostasis in the kidney. J. Biol. Chem. 288: 36202-36214, 2013. [PubMed: 24163368] [Full Text: https://doi.org/10.1074/jbc.M113.498634]
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You, L., Kruse, F. E. Differential effect of activin A and BMP-7 on myofibroblast differentiation and the role of the Smad signaling pathway. Invest. Ophthal. Vis. Sci. 43: 72-81, 2002. [PubMed: 11773015]
Zeisberg, E. M., Tarnavski, O., Zeisberg, M., Dorfman, A. L., McMullen, J. R., Gustafsson, E., Chandraker, A., Yuan, X., Pu, W. T., Roberts, A. B., Neilson, E. G., Sayegh, M. H., Izumo, S., Kalluri, R. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nature Med. 13: 952-961, 2007. [PubMed: 17660828] [Full Text: https://doi.org/10.1038/nm1613]