BMP antagonists: their roles in development and involvement in pathophysiology

Bone morphogenetic proteins (BMPs) are phylogenetically conserved signaling molecules that belong to the transforming growth factor (TGF)-beta superfamily, and are involved in the cascades of body patterning and morphogenesis. The activities of BMPs are precisely regulated by certain classes of molecules that are recently recognized as BMP antagonists. BMP antagonists function through direct association with BMPs, thus prohibiting BMPs from binding their cognate receptors. In this review, the classification and functions of BMP antagonists will be discussed, especially focusing on the new family of tissue-specific BMP antagonists composed of uterine sensitization-associated gene 1 (USAG-1) and sclerostin.     

Perspectives in the biological function, the technical and therapeutic application of bone morphogenetic proteins

The bone morphogenetic proteins (BMPs) belong to the transforming growth factor beta superfamily of growth and differentiation factors and have been characterized by their ability to induce new bone formation in ectopic (non-skeletal) sites. BMPs are secreted molecules and are key regulators in early embryogenesis and organogenesis. One of the many functions of BMPs is to induce cartilage, bone, and connective tissue formation in vertebrates. This osteo-inductive capacity of BMPs has long been considered very promising for applications in bone repair, in the treatment of skeletal diseases, and in oral applications such as dentiogenesis and cementogenesis during regeneration of periodontal wounds. We discuss here biological roles of the BMPs in the organism and their signaling cascades leading to bone and cartilage formation in particular. It is also the aim of this review to evaluate the potential and the problems of BMPs in skeletal tissue engineering for the regeneration of bone damaged by disease or trauma and to serve as therapeutic agents for periodontal defects.     

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.     

BMP/Smad信号通路与哺乳动物卵泡发生

BMPs属于TGF-b超家族成员, 在调节哺乳动物的生长、细胞增殖和分化等方面有很广泛的生物学功能。越来越多的证据显示, BMPs在雌性哺乳动物生殖, 尤其在卵泡发生过程中发挥重要作用。Smads蛋白是BMP家族细胞内信号转导分子, 可将BMPs胞外信号从细胞膜传递入细胞核。文章对BMPs、BMP/Smad信号通路和BMP如何被调节进行概述, 并重点对BMP/Smad信号通路在卵泡发生过程中所起的调控作用进行综述。     

The BMP signaling and in vivo bone formation

Bone morphogenetic proteins (BMPs) are multi-functional growth factors that belong to the transforming growth factor beta (TGFbeta) superfamily. The roles of BMPs in embryonic development and cellular functions in postnatal and adult animals have been extensively studied in recent years. Signal transduction studies have revealed that Smads 1, 5 and 8 are the immediate downstream molecules of BMP receptors and play a central role in BMP signal transduction. Studies from transgenic and knockout mice and from animals and humans with naturally occurring mutations in BMPs and their signaling molecules have shown that BMP signaling plays critical roles in bone and cartilage development and postnatal bone formation. BMP activities are regulated at different molecular levels. Tissue-specific knockout of a specific BMP ligand, a subtype of BMP receptors or a specific signaling molecule is required to further determine the specific role of a BMP ligand, receptor or signaling molecule in a particular tissue.     

Regulation of epithelial to mesenchymal transition by bone morphogenetic proteins

Epithelial to mesenchymal transition (EMT) is a process in which fully differentiated epithelial cells lose many of their epithelial characteristics and adopt features typical of mesenchymal cells, thus allowing cells to become migratory and invasive. EMT is a critical process in development and its role in cancer and fibrosis is becoming increasingly recognised. It is also becoming apparent that EMT is not just restricted to embryonic development and disease in adults, but in fact may be an important process for the maintenance and regeneration of adult tissue architecture. While transforming growth factor-β (TGF-β) is considered a prototypic inducer of EMT, relatively little is known about other signalling molecules that regulate EMT. Bone morphogenic proteins (BMPs) are members of the TGF-β superfamily and 20 different human BMPs have been identified. Originally named for their effects on bone, these proteins are now considered to be key morphogenetic signals that orchestrate tissue architecture throughout the body. BMP2, -4 and -7 are the best studied to date. There are disparate reports of the roles of BMPs in EMT during development, cancer and fibrosis. Here, we present an overview of this literature as well as the emerging role of EMT in tissue regeneration and the involvement of BMPs in regulating this process.     

Regulation of epithelial stem cells in tooth regeneration

Teeth form as epithelial appendages and the mechanisms regulating their development share similarities with other organs such as hairs, glands, and gut. However, the regenerative potential of mammalian teeth is generally limited. Stem cells have been identified in the epithelium of continuously growing incisors of mice. We have identified a network of signalling molecules that regulates the proliferation and differentiation of these stem cells, and that thereby influences the incisors' growth and enamel formation. The signals, including FGFs, BMPs, and Activin, mediate interactions between the mesenchymal and epithelial cells within the stem cell niche and form an integrated network. Follistatin antagonizes the functions of BMPs and Activin, and is a key regulator of the asymmetry of the incisor structure. The evolutionary variation in the growth capacity of teeth and the extent of enamel deposition may have resulted from fine-tuning of this signal network. In addition, subtle variations in this or in related regulatory networks may explain the different regenerative capacities of various organs and animal species.     

Mechanisms of bone metastasis formation

Bone is a common metastatic site for many cancers. Tumor cells located in the bone marrow cavity disturb the natural balance (bone remodelling) established between new bone formation performed by osteoblasts and bone resorption carried out by osteoclasts. Tumor cells produce many factors including growth factors and cytokines (PTHrP, ET-1, BMPs, others...) that stimulate either ostoclast activity leading to osteolytic lesions or osteoblast activity generating osteosclerotic bone metastases. Growth factors released from resorbed bone matrix or throughout osteoblastic bone formation sustain tumor growth. Therefore, bone metastases are the site of vicious cycles wherein tumor growth and bone metabolism sustain each other.     

Use of bone morphogenetic proteins in mesenchymal stem cell stimulation of cartilage and bone repair

The extracellular matrix-associated bone morphogenetic proteins(BMPs) govern a plethora of biological processes. The BMPs are members of the transforming growth factor-β protein superfamily, and they actively participate to kidney development, digit and limb formation, angiogenesis, tissue fibrosis and tumor development. Since their discovery, they have attracted attention for their fascinating perspectives in the regenerative medicine and tissue engineering fields. BMPs have been employed in many preclinical and clinical studies exploring their chondrogenic or osteoinductive potential in several animal model defects and in human diseases. During years of research in particular two BMPs, BMP2 and BMP7 have gained the podium for their use in the treatment of various cartilage and bone defects. In particular they have been recently approved for employment in non-union fractures as adjunct therapies. On the other hand, thanks to their potentialities in biomedical applications, there is a growing interest in studying the biology of mesenchymal stem cell(MSC), the rules underneath their differentiation abilities, and to test their true abilities in tissue engineering. In fact, the specific differentiation of MSCs into targeted celltype lineages for transplantation is a primary goal of the regenerative medicine. This review provides an overview on the current knowledge of BMP roles and signaling in MSC biology and differentiation capacities. In particular the article focuses on the potential clinical use of BMPs and MSCs concomitantly, in cartilage and bone tissue repair.     

Cell responses to bone morphogenetic proteins and peptides derived from them: Biomedical applications and limitations

The bone morphogenetic proteins (BMPs) are cytokines of the transforming growth factor beta family. Some BMPs such as BMP-2 and BMP-7 play a major role in the development of the skeleton and the maintenance of homeostasis during bone remodelling. To date, only BMP-2 and BMP-7 have been approved by the Food and Drug Administration for specific orthopaedic applications. However, due to BMP cost, peptides derived from their knuckle epitope with osteogenic properties have been developed. BMPs are involved in many other biological events, including embryogenesis, angiogenesis and cancer. BMPs therefore have great biomedical potential as osteogenic factors and as anti-cancer agents. This review focuses on the use of BMPs and their derived peptides in biomedical delivery systems and gene therapy.     

Efficient and stable display of functional proteins on bacterial magnetic particles using mms13 as a novel anchor molecule

Magnetic particles are increasingly used for various biomedical applications because they are easy to handle and separate from biological samples. In this work, a novel anchor molecule was used for targeted protein display onto magnetic nanoparticles. The magnetic bacterium Magnetospirillum magneticum AMB-1 synthesizes intracellular bacterial magnetic particles (BMPs) covered with a lipid bilayer membrane. In our recent research, an integral BMP membrane protein, Mms13, was isolated and used as an anchor molecule to display functional proteins onto BMPs. The anchoring properties of Mms13 were confirmed by luciferase fusion studies. The C terminus of Mms13 was shown to be expressed on the surface of BMPs, and Mms13 was bound to magnetite directly and tightly permitting stable localization of a large protein, luciferase (61 kDa), on BMPs. Consequently, luminescence intensity obtained from BMPs using Mms13 as an anchor molecule was >400 or 1,000 times higher than Mms16 or MagA, which previously were used as anchor molecules. Furthermore, the immunoglobulin G-binding domain of protein A (ZZ) was displayed uniformly on BMPs using Mms13, and antigen was detected by transmission electron microscopy using antibody-labeled gold nanoparticles on a single BMP displaying the ZZ-antibody complex. The results of this study demonstrated the utility of Mms13 as a molecular anchor, which will facilitate the assembly of other functional proteins onto BMPs in the near feature.     

A silent H-bond can be mutationally activated for high-affinity interaction of BMP-2 and activin type IIB receptor

Background  

Bone morphogenetic proteins (BMPs) are key regulators in the embryonic development and postnatal tissue homeostasis in all animals. Loss of function or dysregulation of BMPs results in severe diseases or even lethality. Like transforming growth factors β (TGF-βs), activins, growth and differentiation factors (GDFs) and other members of the TGF-β superfamily, BMPs signal by assembling two types of serine/threonine-kinase receptor chains to form a hetero-oligomeric ligand-receptor complex. BMP ligand receptor interaction is highly promiscuous, i.e. BMPs bind more than one receptor of each subtype, and a receptor bind various ligands. The activin type II receptors are of particular interest, since they bind a large number of diverse ligands. In addition they act as high-affinity receptors for activins but are also low-affinity receptors for BMPs. ActR-II and ActR-IIB therefore represent an interesting example how affinity and specificity might be generated in a promiscuous background.     

Efficient and Stable Display of Functional Proteins on Bacterial Magnetic Particles Using Mms13 as a Novel Anchor Molecule

Magnetic particles are increasingly used for various biomedical applications because they are easy to handle and separate from biological samples. In this work, a novel anchor molecule was used for targeted protein display onto magnetic nanoparticles. The magnetic bacterium Magnetospirillum magneticum AMB-1 synthesizes intracellular bacterial magnetic particles (BMPs) covered with a lipid bilayer membrane. In our recent research, an integral BMP membrane protein, Mms13, was isolated and used as an anchor molecule to display functional proteins onto BMPs. The anchoring properties of Mms13 were confirmed by luciferase fusion studies. The C terminus of Mms13 was shown to be expressed on the surface of BMPs, and Mms13 was bound to magnetite directly and tightly permitting stable localization of a large protein, luciferase (61 kDa), on BMPs. Consequently, luminescence intensity obtained from BMPs using Mms13 as an anchor molecule was >400 or 1,000 times higher than Mms16 or MagA, which previously were used as anchor molecules. Furthermore, the immunoglobulin G-binding domain of protein A (ZZ) was displayed uniformly on BMPs using Mms13, and antigen was detected by transmission electron microscopy using antibody-labeled gold nanoparticles on a single BMP displaying the ZZ-antibody complex. The results of this study demonstrated the utility of Mms13 as a molecular anchor, which will facilitate the assembly of other functional proteins onto BMPs in the near feature.     

The bone morphogenetic protein family and osteogenesis.

The BMPs (bone morphogenetic proteins) are a group of related proteins originally identified by their presence in bone-inductive extracts of demineralized bone. By molecular cloning, at least six related members of this family have been identified and are called BMP-2 through BMP-7. These molecules are part of the TGF-beta superfamily, based on primary amino acid sequence homology, including the absolute conservation of seven cysteine residues between the TGF-betas and the BMPs. The BMPs can be divided into subgroups with BMP-2 and BMP-4 being 92% identical, and BMP-5, BMP-6, and BMP-7 being an average of about 90% identical. To examine the individual activities of these molecules, we are producing each BMP in a mammalian expression system. In this system, each BMP is synthesized as a precursor peptide, which is glycosylated, processed to the mature peptide, and secreted as a homodimer. These reagents have been used to demonstrate that single molecules, such as BMP-2, are capable of inducing the formation of new cartilage and bone when implanted ectopically in a rodent assay system. Whether each of the BMPs possesses the same inductive activities in an animal is the subject of ongoing research. Based on the chondrogenic and osteogenic abilities of the BMPs in the adult animal, the expression of the mRNAs for the BMPs has been examined in the development of the embryonic skeleton by in situ hybridization. These studies demonstrate that the BMP mRNAs are spatially and temporally expressed appropriately for the proteins involved in the induction and development of cartilage and bone in the embryonic limb bud.(ABSTRACT TRUNCATED AT 250 WORDS)     

Coordinate regulation of neural tube patterning and proliferation by TGFbeta and WNT activity

Pattern formation and growth must be tightly coupled during embryonic development. In vertebrates, however, little is known of the molecules that serve to link these two processes. Here we show that bone morphogenetic proteins (BMP) coordinate the acquisition of pattern information and the stimulation of proliferation in the embryonic spinal neural tube. We have blocked BMP and transforming growth factor-β superfamily (TGFβ) function in the chick embryo using Noggin, a BMP antagonist, and siRNA against Smad4. We show that BMPs/TGFβs are necessary to regulate pattern formation and the specification of neural progenitor populations in the dorsal neural tube. BMPs also serve to establish discrete expression domains of Wnt ligands, receptors, and antagonists along the dorsal-ventral axis of the neural tube. Using the extracellular domain of Frizzled 8 to block Wnt signaling and Wnt3a ligand misexpression to activate WNT signaling, we demonstrate that the Wnt pathway acts mitogenically to expand the populations of neuronal progenitor cells specified by BMP. Thus, BMPs, acting through WNTs, couple patterning and growth to generate dorsal neuronal fates in the appropriate proportions within the neural tube.     

A new model for growth factor activation: type II receptors compete with the prodomain for BMP-7

Bone morphogenetic proteins (BMPs) are morphogens with long-range signaling activities. BMP-7 is secreted as a stable complex consisting of a growth factor noncovalently associated with two propeptides. In other transforming growth factor-β-like growth factor complexes, the prodomain (pd) confers latency to the complex. However, we detected no difference in signaling capabilities between the growth factor and the BMP-7 complex in multiple in vitro bioactivity assays. Biochemical and biophysical methods elucidated the interaction between the BMP-7 complex and the extracellular domains of its type I and type II receptors. Results showed that type II receptors, such as BMP receptor II, activin receptor IIA, and activin receptor IIB, competed with the pd for binding to the growth factor and displaced the pd from the complex. In contrast, type I receptors interacted with the complex without displacing the pd. These studies suggest a new model for growth factor activation in which proteases or other extracellular molecules are not required and provide a molecular mechanism consistent with a role for BMP receptors in the establishment of early morphogen gradients.