Bone Morphogenetic Proteins

Bone Morphogenetic Protein (BMP) refers to an activity derived from bone that induces the formation of cartilage and bone in vivo. This activity leads to a series of developmental processes including chemotaxis, proliferation, and differentiation, which result in the transient formation of cartilage and the production of living bone tissue, complete with hematopoietic marrow. The determination of the factor or factors responsible for this activity has clear significance both for our understanding of bone biology and for the clinical application of cartilage and bone replacement. Several newly discovered factors, BMP-1, BMP-2 (BMP-2A), BMP-3 (osteogenin), BMP-4 (BMP-2B), BMP-5, BMP-6, BMP-7, and osteoinductive factor (OIF) have been implicated in the BMP process. BMP-2 through BMP-7 are all in the TGF-β superfamily of molecules, and are closely related to two factors (Vg1 and dpp) which are involved in a variety of developmental processes during embryogenesis. A recently discovered factor, OIF, exhibits BMP activity only in the presence of TGF-β. BMP-2, expressed as a recombinant protein, is the only molecule described to date that has been shown to clearly induce by itself the entire cartilage and bone formation process seen with bone-derived BMP. Evidence is accumulating that the BMP effect is a result of the combined actions of a set of BMP-2-like molecules. Definitive examination of the activities of the other factors will require expression of the recombinant proteins and testing of these in vivo alone and in combinations.     

骨形态发生蛋白在脂肪生成中的作用

骨形态发生蛋白（bone morphogenesis proteins, BMP）是一类多功能生长因子,除BMP1外都属于转化生长因子β（transforming growth factor beta, TGFβ）超家族的成员. 近年来,越来越多的研究表明,BMP在脂肪生成过程中也起着重要的作用. 本文综述了BMP在诱导间充质干细胞（mesenchymal stem cells, MSC）、脂肪前体细胞系和胚胎干细胞（embryonic stem cells, ESC）生成脂肪细胞的过程中的作用及信号通路方面的研究进展.这些结果将有助于了解不同部位脂肪沉积的调控机制以及一些脂肪过多疾病（如肥胖症）的产生原因     

Bone Morphogenetic Proteins Stimulate Mammary Fibroblasts to Promote Mammary Carcinoma Cell Invasion

Bone Morphogenetic Proteins (BMPs) are secreted cytokines that are part of the Transforming Growth Factor β (TGFβ) superfamily. BMPs have been shown to be highly expressed in human breast cancers, and loss of BMP signaling in mammary carcinomas has been shown to accelerate metastases. Interestingly, other work has indicated that stimulation of dermal fibroblasts with BMP can enhance secretion of pro-tumorigenic factors. Furthermore, treatment of carcinoma-associated fibroblasts (CAFs) derived from a mouse prostate carcinoma with BMP4 was shown to stimulate angiogenesis. We sought to determine the effect of BMP treatment on mammary fibroblasts. A large number of secreted pro-inflammatory cytokines and matrix-metallo proteases (MMPs) were found to be upregulated in response to BMP4 treatment. Fibroblasts that were stimulated with BMP4 were found to enhance mammary carcinoma cell invasion, and these effects were inhibited by a BMP receptor kinase antagonist. Treatment with BMP in turn elevated pro-tumorigenic secreted factors such as IL-6 and MMP-3. These experiments demonstrate that BMP may stimulate tumor progression within the tumor microenvironment.     

A Meta Analysis of Lumbar Spinal Fusion Surgery Using Bone Morphogenetic Proteins and Autologous Iliac Crest Bone Graft

BackgroundBone morphogenetic protein (BMPs) as a substitute for iliac crest bone graft (ICBG) has been increasingly widely used in lumbar fusion. The purpose of this study is to systematically compare the effectiveness and safety of fusion with BMPs for the treatment of lumbar disease.MethodsCochrane review methods were used to analyze all relevant randomized controlled trials (RCTs) published up to nov 2013.Results19 RCTs (1,852 patients) met the inclusion criteria. BMPs group significantly increased fusion rate (RR: 1.13; 95% CI 1.05–1.23, P = 0.001), while there was no statistical difference in overall success of clinical outcomes (RR: 1.04; 95% CI 0.95–1.13, P = 0.38) and complications (RR: 0.96; 95% CI 0.85–1.09, p = 0.54). A significant reduction of the reoperation rate was found in BMPs group (RR: 0.57; 95% CI 0.42–0.77, p = 0.0002). Significant difference was found in the operating time (MD−0.32; 95% CI−0.55, −0.08; P = 0.009), but no significant difference was found in the blood loss, the hospital stay, patient satisfaction, and work status.ConclusionCompared with ICBG, BMPs in lumbar fusion can increase the fusion rate, while reduce the reoperation rate and operating time. However, it doesn’t increase the complication rate, the amount of blood loss and hospital stay. No significant difference was found in the overall success of clinical outcome of the two groups.     

骨形态发生蛋白在多器官组织分化发育中的作用及研究进展

骨形态发生蛋白(Bone morphogenetic proteins,BMPs)是一种多功能蛋白,是转化生长因子TGF-β超家族成员,参与骨器官发生、形成与再生的过程,同时对神经系统、造血系统的分化发育也有调控作用.目前,BMPs的研究已经涉及发育生物学、遗传学等多个领域,并在临床上具有广泛的应用前景.基于相关研究近状,对BMPs的分子结构特征及其在多器官组织分化发育中的作用进行分析,为进一步研究BMPs的体内活性及临床应用提供了理论借鉴和参考.     

The Controversy Surrounding Bone Morphogenetic Proteins in the Spine: A Review of Current Research

Bone morphogenetic proteins have been in use in spinal surgery since 2002. These proteins are members of the TGF-beta superfamily and guide mesenchymal stem cells to differentiate into osteoblasts to form bone in targeted tissues. Since the first commercial BMP became available in 2002, a host of research has supported BMPs and they have been rapidly incorporated in spinal surgeries in the United States. However, recent controversy has arisen surrounding the ethical conduct of the research supporting the use of BMPs. Yale University Open Data Access (YODA) recently teamed up with Medtronic to offer a meta-analysis of the effectiveness of BMPs in spinal surgery. This review focuses on the history of BMPs and examines the YODA research to guide spine surgeons in their use of BMP in spinal surgery.     

Repulsive Guidance Molecule (RGM) Family Proteins Exhibit Differential Binding Kinetics for Bone Morphogenetic Proteins (BMPs)

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor beta superfamily that exert their effects via type I and type II serine threonine kinase receptors and the SMAD intracellular signaling pathway to regulate diverse biologic processes. Recently, we discovered that the repulsive guidance molecule (RGM) family, including RGMA, RGMB, and RGMC/hemojuvelin (HJV), function as co-receptors that enhance cellular responses to BMP ligands. Here, we use surface plasmon resonance to quantitate the binding kinetics of RGM proteins for BMP ligands. We show that among the RGMs, HJV exhibits the highest affinity for BMP6, BMP5, and BMP7 with K_D 8.1, 17, and 20 nM respectively, versus 28, 33, and 166 nM for RGMB, and 55, 83, and 63 nM for RGMA. Conversely, RGMB exhibits preferential binding to BMP4 and BMP2 with K_D 2.6 and 5.5 nM respectively, versus 4.5 and 9.4 nM for HJV, and 14 and 22 nM for RGMA, while RGMA exhibits the lowest binding affinity for most BMPs tested. Among the BMP ligands, RGMs exhibit the highest relative affinity for BMP4 and the lowest relative affinity for BMP7, while none of the RGMs bind to BMP9. Thus, RGMs exhibit preferential binding for distinct subsets of BMP ligands. The preferential binding of HJV for BMP6 is consistent with the functional role of HJV and BMP6 in regulating systemic iron homeostasis. Our data may help explain the mechanism by which BMPs exert cell-context specific effects via a limited number of type I and type II receptors.     

Dual Role of Jun N-Terminal Kinase Activity in Bone Morphogenetic Protein-Mediated Drosophila Ventral Head Development

The Drosophila bone morphogenetic protein encoded by decapentaplegic (dpp) controls ventral head morphogenesis by expression in the head primordia, eye-antennal imaginal discs. These are epithelial sacs made of two layers: columnar disc proper cells and squamous cells of the peripodial epithelium. dpp expression related to head formation occurs in the peripodial epithelium; cis-regulatory mutations disrupting this expression display defects in sensory vibrissae, rostral membrane, gena, and maxillary palps. Here we document that disruption of this dpp expression causes apoptosis in peripodial cells and underlying disc proper cells. We further show that peripodial Dpp acts directly on the disc proper, indicating that Dpp must cross the disc lumen to act. We demonstrate that palp defects are mechanistically separable from the other mutant phenotypes; both are affected by the c-Jun N-terminal kinase pathway but in opposite ways. Slight reduction of both Jun N-terminal kinase and Dpp activity in peripodial cells causes stronger vibrissae, rostral membrane, and gena defects than Dpp alone; additionally, strong reduction of Jun N-terminal kinase activity alone causes identical defects. A more severe reduction of dpp results in similar vibrissae, rostral membrane, and gena defects, but also causes mutant maxillary palps. This latter defect is correlated with increased peripodial Jun N-terminal kinase activity and can be caused solely by ectopic activation of Jun N-terminal kinase. We conclude that formation of sensory vibrissae, rostral membrane, and gena tissue in head morphogenesis requires the action of Jun N-terminal kinase in peripodial cells, while excessive Jun N-terminal kinase signaling in these same cells inhibits the formation of maxillary palps.     

Inhibitors of Myelination and Remyelination,Bone Morphogenetic Proteins,are Upregulated in Human Neurological Disease

Neurochemical Research - During demyelinating disease such as multiple sclerosis and stroke, myelin is destroyed and along with it, the oligodendrocytes that synthesize the myelin. Thus, recovery...     

骨形态发生蛋白-7的研究进展

骨形态发生蛋白是近来研究较多的一种生物因子,属于TGF—β超家族的一员。最初发现的作用是异位诱导成骨,并根据这一特点应用于临床一些难治性骨缺损疾病的治疗。其成员BMP—7作为一种细胞因子,在与体内其他因子作用的基础上,对其他多种组织的发育及功能均有重要作用。     

Metformin attenuates trauma‐induced heterotopic ossification via inhibition of Bone Morphogenetic Protein signalling

AMP‐activated protein kinase (AMPK) is an intracellular sensor of energy homoeostasis that is activated under energy stress and suppressed in energy surplus. AMPK activation leads to inhibition of anabolic processes that consume ATP. Osteogenic differentiation is a process that highly demands ATP during which AMPK is inhibited. The bone morphogenetic proteins (BMPs) signalling pathway plays an essential role in osteogenic differentiation. The present study examines the inhibitory effect of metformin on BMP signalling, osteogenic differentiation and trauma‐induced heterotopic ossification. Our results showed that metformin inhibited Smad1/5 phosphorylation induced by BMP6 in osteoblast MC3T3‐E1 cells, concurrent with up‐regulation of Smad6, and this effect was attenuated by knockdown of Smad6. Furthermore, we found that metformin suppressed ALP activity and mineralization of the cells, an event that was attenuated by the dominant negative mutant of AMPK and mimicked by its constitutively active mutant. Finally, administration of metformin prevented the trauma‐induced heterotopic ossification in mice. In conjuncture, AMPK activity and Smad6 and Smurf1 expression were enhanced by metformin treatment in the muscle of injured area, concurrently with the reduction of ALK2. Collectively, our study suggests that metformin prevents heterotopic ossification via activation of AMPK and subsequent up‐regulation of Smad6. Therefore, metformin could be a potential therapeutic drug for heterotopic ossification induced by traumatic injury.     

Immunohistochemical Localization of Bone Morphogenetic Proteins (BMPs) and their Receptors in Solitary and Multiple Human Osteochondromas

The expression of bone morphogenetic proteins (BMPs) and their cognate receptors (BMPRs) in osteochondromas has not been investigated. We determined the immunohistochemical localization and distribution of BMP-2/4, -6 and -7; BMP receptors BMPR-1A, BMPR-1B and BMPR-2; signal transducing proteins phosphorylated Smad1/5/8; and BMP antagonist noggin in the cartilaginous cap of solitary (SO) and multiple (MO) human osteochondromas and compared these with bovine growth plate and articular cartilage. The distribution and localization patterns for BMP-6, BMP-7, BMPR-1A and BMPR-2 were similar between the cartilaginous cap and the growth plate. BMP-2/4 and BMPR-1B were present throughout the growth plate. However, BMP-2/4 and phosphorylated Smad1/5/8 were mainly detected in proliferating chondrocytes of the cartilaginous cap. Also, BMPR-1B was found in hypertrophic chondrocytes of SO and proliferating chondrocytes of MO. Noggin was observed in resting chondrocytes and, to a lesser extent, in clustered proliferating chondrocytes in SO. On the other hand, noggin in MO was observed in proliferating chondrocytes. Since BMPs can stimulate proliferation and hypertrophic differentiation of chondrocytes, these findings suggest that there is an imbalance of BMP-2/4 and noggin interactions that may lead to abnormal regulation of chondrocyte proliferation and differentiation in the cartilaginous cap of human osteochondromas.     

FRET Reveals Novel Protein-Receptor Interaction of Bone Morphogenetic Proteins Receptors and Adaptor Protein 2 at the Cell Surface

Bone morphogenetic proteins (BMPs) are involved with a wide range of processes including apoptosis, differentiation, and proliferation. Several different pathways such as Smad, p38, and PI3/Akt are activated by BMPs. Signaling is transduced by BMP receptors (BMPRs) of type I and type II that are serine/threonine kinase receptors. BMPRs shuttle between membrane domains such as caveolae enriched with caveolin-1 β-isoform and caveolae of the caveolin-1 α/β-isoforms. It is hypothesized that there are other membrane domains to which the receptors localize. We used immunoprecipitation, Western blots, image cross-correlation spectroscopy, and fluorescence resonance energy transfer to investigate the interaction of BMPRs with proteins in clathrin-coated pits (CCPs). Our data indicate that these domains are associated with at least two of the BMPRs: BRIa and BRII. For the first time, to our knowledge, we showed what we believe are specific interactions between BRIa and BRII with a key component of CCPs, adaptor protein 2. Further, disruption of CCPs resulted in increased BRIa aggregation at the cell surface and activation of the BMP pathway even in the absence of BMP2. Therefore, CCPs seem to function as a negative regulatory membrane domain for BMP pathway activation.     

骨形成蛋白15基因的研究进展

骨形成蛋白是属于转移生长因子-β超家族生长因子的一种分泌型信号分子。迄今为止,已有30多个骨形成蛋白被确定,骨形成蛋白15基因在卵母细胞中表达,具有推动卵泡生长,阻止黄体早熟的作用。本文综述了骨形成蛋白15基因的研究现状。 Abstract:Bone morphogenetic proteins (BMPs) are secreted signalling molecules belonging to the transforming growth factor-β (TGF-β) surperfamily.Up to date,more than 30 members of BMPs are identified.Bone morphogenetic protein-15 is only expressed in oocytes.Oocyte-specific BMP-15 might promote follicle growth in vivo,while preventing premature luteinization.This paper biefly discusses the progress in the research area of BMP-15 gene being as a candidate gene for litter size.     

Modeling the Early Stages of Phase Separation in Disordered Elastin-like Proteins

Elastin-like proteins (ELPs) are known to undergo liquid-liquid phase separation reversibly above a concentration-dependent transition temperature. Previous studies suggested that, as temperature increases, ELPs experience an increased propensity for type II β-turns. However, how the ELPs behave below the phase transition temperature itself is still elusive. Here, we investigate the importance of β-turn formation during the early stages of ELP self-association. We examined the behavior of two ELPs, a 150-repeat construct that had been investigated previously (ELP[V₅G₃A₂-150] as well as a new 40-repeat construct (ELP40) suitable for nuclear magnetic resonance measurements. Structural analysis of ELP40 reveals a disordered conformation, and chemical shifts throughout the sequence are insensitive to changes in temperature over 20°C. However, a low population of β-turn conformation cannot be ruled out based on chemical shifts alone. To examine the structural consequences of β-turns in ELPs, a series of structural ensembles of ELP[V₅G₃A₂-150] were generated, incorporating differing amounts of β-turn bias throughout the chain. To mimic the early stages of the phase change, two monomers were paired, assuming preferential interaction at β-turn regions. This approach was justified by the observation that buried hydrophobic turns are commonly observed to interact in the Protein Data Bank. After dimerization, the ensemble-averaged hydrodynamic properties were calculated for each degree of β-turn bias, and the results were compared with analytical ultracentrifugation experiments at various temperatures. We find that the temperature dependence of the sedimentation coefficient $\left(s_{20,\text{w}}^{\text{o}}\right)$ can be reproduced by increasing the β-turn content in the structural ensemble. This analysis allows us to estimate the presence of β-turns and weak associations under experimental conditions. Because disordered proteins frequently exhibit weak biases in secondary structure propensity, these experimentally-driven ensemble calculations may complement existing methods for modeling disordered proteins generally.     

骨形成蛋白-15基因研究进展

骨形成蛋白-15(BMP-15)是属于转移生长因子-β超家族生长因子的一种分泌型信号分子,仅在卵母细胞中特异性表达,具有促进卵泡生长,阻止黄体早熟的作用。开展对BMP-15基因的研究将有助于人们从基因角度阐明不育或多胎的形成和发展机制,对医学和畜牧业等领域将产生积极的影响。从BMP基因控制排卵数的机制入手,总结BMP-15基因的研究进展。