Disease relevance of Bmp2

• Both the fetal and adult compound-deficient mice showed a reduction in the trabecular bone volume with suppressed bone formation, but normal bone resorption, whereas the single deficient mice (Bmp2+/- or Bmp6-/-) did not [1].
• These findings suggest that BMP-2, in concert with TNF, plays an essential role in regulating the regeneration of peripheral nerves following injury with bone fracture through an indirect mechanism by which it stimulates NGF production in fibroblasts [2].
• Using retroviruses or beads to increase Fibroblast Growth Factors (FGFs) for gain-of-function and beads soaked with the FGF inhibitor SU5402 for loss-of-function experiments, we show that FGFs in the crista promote canal development by upregulating Bmp2 [3].
• Transcriptional regulation of the Bmp2 gene. Retinoic acid induction in F9 embryonal carcinoma cells and Saccharomyces cerevisiae [4].
• Hypoxia promoted bone morphogenetic protein 2-induced glycosaminoglycan production and suppressed alkaline phosphatase activity and mineralization of C3H10T1/2 [5].

High impact information on Bmp2

• In fact, in bones lacking BMP2, the earliest steps of fracture healing seem to be blocked [6].
• Mice lacking the ability to produce BMP2 in their limb bones have spontaneous fractures that do not resolve with time [6].
• Lack of Fgf8 in the apical ectodermal ridge (AER) alters expression of other Fgf genes, Shh and Bmp2 [7].
• We demonstrate that bone morphogenic protein 2 (BMP2) induces the basic-helix-loop-helix protein MASH1 and neurogenesis in neural crest stem cells [8].
• Some smooth muscle differentiation is also observed in BMP2 [8].

Chemical compound and disease context of Bmp2

• C3 cells infected with adenovirus vector encoding BMP-2 (AdBMP-2) or Runx2 (AdRunx2) showed greatly increased ALP mRNA expression in a time-dependent fashion [9].
• Regulation of the laminin beta 1 (LAMB1), retinoic acid receptor beta, and bone morphogenetic protein 2 genes in mutant F9 teratocarcinoma cell lines partially deficient in cyclic AMP-dependent protein kinase activity [10].

Biological context of Bmp2

• In the foot plates of the mutant homozygotes, both Bmp2 and Bmp7 expression and apoptotic interdigital cell death are reduced [11].
• Analysis of the loss-of-function phenotype in mouse embryos homozygous for targeted disruption of Hey2 revealed an expanded AVC domain of Bmp2 [12].
• Runx2 regulates FGF2-induced Bmp2 expression during cranial bone development [13].
• In addition, cultured Runx2-/- cells expressed very low baseline levels of Bmp2 that were up-regulated by transfection with a Runx2-expressing plasmid [13].
• Taken together, these results indicate that Gli2 mediates hedgehog signaling in osteoblasts and is a powerful activator of BMP-2 gene expression, which is required in turn for normal osteoblast differentiation [14].

Anatomical context of Bmp2

• To address the function of bone morphogenetic protein-2 (BMP2) in mammalian development, mice with a targeted deletion of the Bmp2 mature region were generated using embryonic stem cell technology [15].
• These defects are consistent with the expression of Bmp2 in the extraembryonic mesoderm cells and promyocardium [15].
• In further analyses, we have identified Bmp2 as the factor required for production of migratory cranial neural crest [16].
• In the Hesr1-misexpressing heart, the boundaries of the AV canal are poorly defined, and the expression levels of specific markers of the AV myocardium, Bmp2 and Tbx2, are either very weak or undetectable [17].
• In addition, we provide evidence that Hedgehog signaling, acting at the Shh boundary within the oral ectoderm, may exert a role in differentiation of ventral cell types (gonadotropes and thyrotropes) by inducing Bmp2 expression in Rathke's pouch, which subsequently regulates expression of ventral transcription factors, particularly Gata2 [18].

Associations of Bmp2 with chemical compounds

• Retinoic acid application, which mimics the effects of polarizing region grafts, activates Bmp-2 gene expression in anterior cells [19].
• Cyp17 mRNA endogenously expressed by AC cells was suppressed by activins A and B and BMP-2, -6, and -7, and each ligand accordingly inhibited 17alpha-hydroxyprogesterone production (IC(50) of 0.24, 0.27, 0.4, 0.51, and 2.2 nm, respectively) [20].
• We have investigated the effect of 1-(5-oxohexyl)-3,7-dimethylxanthine or pentoxifylline (PeTx), a nonselective phosphodiesterase inhibitor, on osteoblastic differentiation in vitro by using two mesenchymal cell lines, C3H10T1/2 and C2C12, which are able to acquire the osteoblastic phenotype in the presence of bone morphogenetic protein-2 (BMP-2) [21].
• Twisted gastrulation (Tsg) is a secreted glycoprotein that binds bone morphogenetic protein-2 (BMP-2) and BMP-4 and can display both BMP agonist and antagonist functions [22].
• Addition of NS-398 inhibited the expression of the ODF gene in osteoblast-like cells treated with BMP-2 and IL-1alpha [23].

Physical interactions of Bmp2

• Parathyroid hormone-related peptide interacts with bone morphogenetic protein 2 to increase osteoblastogenesis and decrease adipogenesis in pluripotent C3H10T 1/2 mesenchymal cells [24].
• Electrophoresis mobility shift assays indicated that BMP2 treatment on C3H10T1/2 cells increases the binding of cell nuclear extracts to the -148/-42 fragment, and the BMP2-enhanced binding bands are Sp1 transcription factors [25].
• These data indicate that the extracellular domain of type I receptor for BMP-2 and BMP-4 is sufficient for high-affinity binding to its ligands and should prove useful in understanding the role of BMP-2/4 in vivo, because a suitable high-affinity anti-BMP antibody has yet to be developed [26].

Regulatory relationships of Bmp2

• Transfection studies show BMP-2 suppresses OC promoter activity in C2C12, but not in osteoblastic ROS 17/2.8 cells [27].
• Differential roles of Smad1 and p38 kinase in regulation of peroxisome proliferator-activating receptor gamma during bone morphogenetic protein 2-induced adipogenesis [28].
• BMP-2 completely inhibited the expression of myogenin mRNA by day 3 [29].
• By day 3, BMP-2 also inhibited the expression of MyoD mRNA, but it was transiently stimulated 12 h after exposure to BMP-2 [29].
• Since BMP-2 alone induced the expression of COX-2 and ODF genes in osteoblast-like cells, it appears to be one of the regulating factors of osteoclastogenesis [23].

Other interactions of Bmp2

• FGF-4 and BMP-2 have opposite effects on limb growth [30].
• Subsequently, a BMP2 signal emanates from a ventral pituitary organizing center that forms at the boundary of a region of oral ectoderm in which Shh expression is selectively excluded [31].
• The zinc finger transcription factor Gli2 mediates bone morphogenetic protein 2 expression in osteoblasts in response to hedgehog signaling [14].
• As a result, genes such as Bmp2 or Hoxd genes are expressed symmetrically along the AP axis of the forelimb buds, and/or later, of the autopod [32].
• There is a close relationship, both temporal and spatial, between the activation of the Bmp-2 and Hoxd-13 genes in response to retinoic acid and polarizing region grafts, suggesting that expression of the two genes might be linked [19].

Analytical, diagnostic and therapeutic context of Bmp2

• Using whole-mount in situ hybridization, we show that Bmp2 is primarily expressed in the endoderm of mouse pregastrula and gastrula embryos [33].
• Using gene targeting in mouse embryonic stem (ES) cells, we introduced LoxP sites upstream and downstream of Bmp2 exon 3 that encodes the mature peptide [34].
• Promoter analyses, including chromatin immunoprecipitation and electrophoretic mobility shift assays, provided direct evidence that Gli2 physically interacts with the BMP-2 promoter [14].
• Transplantation of BMP-2 (1 microg) into muscle of mice induced formation of ectopic bone, whereas transplantation of r-SHH-N (1-5 microg) failed to generate it [35].
• In this study, we examined the effect of BMP-2 on osteoclast-like multinucleated cell (OCL) formation in cocultures of osteoblast-like cells and hematopoietic cells of bone marrow origin [23].

References