The classic: Bone morphogenetic protein.
Ontology highlight
ABSTRACT:
SUBMITTER: Urist MR
PROVIDER: S-EPMC2772914 | biostudies-other | 2009 Dec
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Bone morphogenetic proteins (BMPs) are an important family of growth factors playing a role in a large number of physiological and pathological processes, including bone homeostasis, tissue regeneration, and cancers. In vivo, BMPs bind successively to both BMP receptors (BMPRs) of type I and type II, and a promiscuity has been reported. In this study, we used biolayer interferometry to perform parallel real-time biosensing and to deduce the kinetic parameters (ka, kd) and the equilibrium constant (KD) for a large range of BMP/BMPR combinations in similar experimental conditions. We selected four members of the BMP family (BMP-2, 4, 7, 9) known for their physiological relevance and studied their interactions with five type-I BMP receptors (ALK1, 2, 3, 5, 6) and three type-II BMP receptors (BMPR-II, ACTR-IIA, ACTR-IIB). We reveal that BMP-2 and BMP-4 behave differently, especially regarding their kinetic interactions and affinities with the type-II BMPR. We found that BMP-7 has a higher affinity for the type-II BMPR receptor ACTR-IIA and a tenfold lower affinity with the type-I receptors. While BMP-9 has a high and similar affinity for all type-II receptors, it can interact with ALK5 and ALK2, in addition to ALK1. Interestingly, we also found that all BMPs can interact with ALK5. The interaction between BMPs and both type-I and type-II receptors in a ternary complex did not reveal further cooperativity. Our work provides a synthetic view of the interactions of these BMPs with their receptors and paves the way for future studies on their cell-type and receptor specific signaling pathways.
| S-EPMC7614001 | biostudies-literature
Project description:Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the transforming growth factor (TGF)-? family of ligands and exert most of their effects through the canonical effectors Smad1, 5, and 8. Appropriate regulation of BMP signaling is critical for the development and homeostasis of numerous human organ systems. Aberrations in BMP pathways or their regulation are increasingly associated with diverse human pathologies, and there is an urgent and growing need to develop effective approaches to modulate BMP signaling in the clinic. In this review, we provide a wide perspective on diseases and/or conditions associated with dysregulated BMP signal transduction, outline the current strategies available to modulate BMP pathways, highlight emerging second-generation technologies, and postulate prospective avenues for future investigation.
| S-EPMC5880173 | biostudies-literature
Project description:Bone morphogenetic proteins (BMPs) are multi-functional growth factors belonging to the Transforming Growth Factor-Beta (TGF-?) superfamily. These proteins are essential to many developmental processes, including cardiogenesis, neurogenesis, and osteogenesis. Specifically, within the BMP family, Bone Morphogenetic Protein-2 (BMP-2) was the first BMP to be characterized and has been well-studied. BMP-2 has important roles during embryonic development, as well as bone remodeling and homeostasis in adulthood. Some of its specific functions include digit formation and activating osteogenic genes, such as Runt-Related Transcription Factor 2 (RUNX2). Because of its diverse functions and osteogenic potential, the Food and Drug Administration (FDA) approved usage of recombinant human BMP-2 (rhBMP-2) during spinal fusion surgery, tibial shaft repair, and maxillary sinus reconstructive surgery. However, shortly after initial injections of rhBMP-2, several adverse complications were reported, and alternative therapeutics have been developed to limit these side-effects. As the clinical application of BMP-2 is largely implicated in bone, we focus primarily on its role in bone. However, we also describe briefly the role of BMP-2 in development. We then focus on the structure of BMP-2, its activation and regulation signaling pathways, BMP-2 clinical applications, and limitations of using BMP-2 as a therapeutic. Further, this review explores other potential treatments that may be useful in treating bone disorders.
| S-EPMC7557435 | biostudies-literature
Project description:Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant human disorder of bone formation that causes developmental skeletal defects and extensive debilitating bone formation within soft connective tissues (heterotopic ossification) during childhood. All patients with classic clinical features of FOP (great toe malformations and progressive heterotopic ossification) have previously been found to carry the same heterozygous mutation (c.617G>A; p.R206H) in the glycine and serine residue (GS) activation domain of activin A type I receptor/activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor. Among patients with FOP-like heterotopic ossification and/or toe malformations, we identified patients with clinical features unusual for FOP. These atypical FOP patients form two classes: FOP-plus (classic defining features of FOP plus one or more atypical features) and FOP variants (major variations in one or both of the two classic defining features of FOP). All patients examined have heterozygous ACVR1 missense mutations in conserved amino acids. While the recurrent c.617G>A; p.R206H mutation was found in all cases of classic FOP and most cases of FOP-plus, novel ACVR1 mutations occur in the FOP variants and two cases of FOP-plus. Protein structure homology modeling predicts that each of the amino acid substitutions activates the ACVR1 protein to enhance receptor signaling. We observed genotype-phenotype correlation between some ACVR1 mutations and the age of onset of heterotopic ossification or on embryonic skeletal development.
| S-EPMC2921861 | biostudies-literature
Project description:Bone morphogenetic proteins (BMPs) belong to the TGF-? family, whose 33 members regulate multiple aspects of morphogenesis. TGF-? family members are secreted as procomplexes containing a small growth factor dimer associated with two larger prodomains. As isolated procomplexes, some members are latent, whereas most are active; what determines these differences is unknown. Here, studies on pro-BMP structures and binding to receptors lead to insights into mechanisms that regulate latency in the TGF-? family and into the functions of their highly divergent prodomains. The observed open-armed, nonlatent conformation of pro-BMP9 and pro-BMP7 contrasts with the cross-armed, latent conformation of pro-TGF-?1. Despite markedly different arm orientations in pro-BMP and pro-TGF-?, the arm domain of the prodomain can similarly associate with the growth factor, whereas prodomain elements N- and C-terminal to the arm associate differently with the growth factor and may compete with one another to regulate latency and stepwise displacement by type I and II receptors. Sequence conservation suggests that pro-BMP9 can adopt both cross-armed and open-armed conformations. We propose that interactors in the matrix stabilize a cross-armed pro-BMP conformation and regulate transition between cross-armed, latent and open-armed, nonlatent pro-BMP conformations.
| S-EPMC4378411 | biostudies-literature
Project description:Bone morphogenetic proteins (BMPs) control multiple cellular processes in embryos and adult tissues. BMPs signal through the activation of type I BMP receptor kinases, which then phosphorylate SMADs 1/5/8. In the canonical pathway, this triggers the association of these SMADs with SMAD4 and their translocation to the nucleus, where they regulate gene expression. BMPs can also signal independently of SMAD4, but this pathway is poorly understood. Here, we report the discovery and characterization of PAWS1/FAM83G as a novel SMAD1 interactor. PAWS1 forms a complex with SMAD1 in a SMAD4-independent manner, and BMP signalling induces the phosphorylation of PAWS1 through BMPR1A. The phosphorylation of PAWS1 in response to BMP is essential for activation of the SMAD4-independent BMP target genes NEDD9 and ASNS. Our findings identify PAWS1 as the first non-SMAD substrate for type I BMP receptor kinases and as a novel player in the BMP pathway. We also demonstrate that PAWS1 regulates the expression of several non-BMP target genes, suggesting roles for PAWS1 beyond the BMP pathway.
| S-EPMC3938053 | biostudies-literature
Project description:The use of growth factors for the regeneration of soft and hard tissues has been utilized extensively in dental medicine over the past decade. Recently our group found that recombinant human bone morphogenetic protein 9 (rhBMP9) was more osteopromotive than recombinant human bone morphogenetic protein 2 (rhBMP2) when combined with a deprotenized bovine bone mineral bone grafting material. The aim of the present in vitro study was to evaluate the regenerative potential of an absorbable collagen sponge(ACS) specifically designed for extraction socket healing loaded with rhBMP9 when compared to rhBMP2. The adsorption and release kinetics of rhBMP2 and rhBMP9 were first investigated by enzyme-linked immunosorbent assay quantification. Then, the cellular effects of stromal cell line (ST2) preosteoblasts were investigated utilizing four groups including rhBMP2 and rhBMP9 at both low(10 ng/ml) and high(100 ng/ml) concentrations loaded onto ACS. Cellular attachment(8 hours) and proliferation(1, 3, and 5 days) as well as osteoblast differentiation were investigated by real-time polymerase chain reaction (PCR) at 3 and 14 days, alkaline phosphatase (ALP) activity at 7 days, and alizarin red staining at 14 days. ACS fully adsorbed both rhBMP2 and rhBMP9 that were slowly released up to 10 days. Although neither rhBMP2 nor rhBMP9 had any effects on cell attachment or proliferation, pronounced effects were observed on osteoblast differentiation. ALP activity was increased seven-fold with rhBMP2-high, whereas a marked 10-fold and 20-fold increase was observed with rhBMP9-low and high loaded to ACS, respectively. Furthermore, mRNA levels of collagen1, ALP, bone sialoprotein, and osteocalcin were all significantly higher for rhBMP9 when compared to control or rhBMP2 groups. Alizarin red staining further confirmed that rhBMP9-low and high demonstrated marked increases in mineralization potential when compared to rhBMP2-high. The results demonstrate the marked effect of rhBMP9 on osteoblast differentiation when combined with ACS in comparison to rhBMP2 at doses as much as 10 times lower. Further in vivo studies are necessary to investigate whether the regenerative potential is equally as potent.
| S-EPMC5839213 | biostudies-literature
Project description:We previously generated a syngeneic preclinical model of NSCLC (p53R172HΔg/+KrasLA1/+) with acquired resistance to anti-PD1. In the current study, we investigated methylation differences in specific genomic regions comparing anti-PD1-resistant tumors (344SQR) with their parental-tumor counterparts (344SQP).
2020-08-17 | GSE154993 | GEO
Project description:In many cases, the level, positioning and timing of signaling through the bone morphogenetic protein (BMP) pathway are regulated by molecules that bind BMP ligands in the extracellular space. Whereas many BMP-binding proteins inhibit signaling by sequestering BMPs from their receptors, other BMP-binding proteins cause remarkably context-specific gains or losses in signaling. Here, we review recent findings and hypotheses on the complex mechanisms that lead to these effects, with data from developing systems, biochemical analyses and mathematical modeling.
| S-EPMC2766339 | biostudies-literature
Project description:Bone Morphogenetic Protein 1 (BMP1) inhibition is a potential method for treating fibrosis because BMP1, a member of the zinc metalloprotease family, is required to convert pro-collagen to collagen. A novel class of reverse hydroxamate BMP1 inhibitors was discovered, and cocrystal structures with BMP1 were obtained. The observed binding mode is unique in that the small molecule occupies the nonprime side of the metalloprotease pocket providing an opportunity to build in metalloprotease selectivity. Structure-guided modification of the initial hit led to the identification of an oral in vivo tool compound with selectivity over other metalloproteases. Due to irreversible inhibition of cytochrome P450 3A4 for this chemical class, the risk of potential drug-drug interactions was managed by optimizing the series for subcutaneous injection.
| S-EPMC6047045 | biostudies-literature