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 Yin and Yang of bone morphogenetic proteins in cancer

Bone morphogenetic proteins (BMPs) were first studied as growth factors or morphogens of the transforming growth factor-beta superfamily. These growth molecules, originally associated with bone and cartilage development, are now known to play an important role in morphogenesis and homeostasis in many other tissues. More recently, significant contributions from BMPs, their receptors, and interacting molecules have been linked to carcinogenesis and tumor progression. On the other hand, BMPs can sometimes function as a tumor suppressor. Our report highlights these new roles in the pathogenesis of cancer that may suggest novel targets for therapeutic intervention.     

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.     

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.     

Bone morphogenetic proteins: a critical review

Bone Morphogenetic Proteins (BMPs) are potent growth factors belonging to the Transforming Growth Factor Beta superfamily. To date over 20 members have been identified in humans with varying functions during processes such as embryogenesis, skeletal formation, hematopoesis and neurogenesis. Though their functions have been identified, less is known regarding levels of regulation at the extracellular matrix, membrane surface, and receptor activation. Further, current models of activation lack the integration of these regulatory mechanisms. This review focuses on the different levels of regulation, ranging from the release of BMPs into the extracellular components to receptor activation for different BMPs. It also highlights areas in research that is lacking or contradictory.     

Multiple functions of BMPs in chondrogenesis

The ability of bone morphogenetic proteins (BMPs) to promote chondrogenesis has been investigated extensively over the past two decades. Although BMPs promote almost every aspect of chondrogenesis, from commitment to terminal differentiation is well known, the mechanisms of BMP action in discrete aspects of endochondral bone formation have only recently begun to be investigated. In this review, we focus on in vivo studies that have identified interactions between BMP signaling pathways and key downstream targets of BMP action in chondrogenesis. We also discuss evidence regarding the potential roles of BMP receptors in mediating distinct aspects of chondrogenesis, and studies investigating the intersection of BMP pathways with other pathways known to coordinate the progression of chondrocytes through the growth plate. These studies indicate that both Smad-dependent and -independent BMP pathways are required for chondrogenesis, and that BMPs exert essential roles via regulation of the Indian hedgehog (IHH)/parathyroid hormone-related protein (PTHrP) and fibroblast growth factor (FGF) pathways in the growth plate.     

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.     

BMP inhibition enhances axonal growth and functional recovery after spinal cord injury

Bone morphogenetic proteins (BMPs) are multifunctional growth factors that belong to the transforming growth factor-β superfamily. BMPs regulate several crucial aspects of embryonic development and organogenesis. The reemergence of BMPs in the injured adult CNS suggests their involvement in the pathogenesis of the lesion. Here, we demonstrate that BMPs are potent inhibitors of axonal regeneration in the adult spinal cord. The expression of BMP-2/4 is elevated in oligodendrocytes and astrocytes around the injury site following spinal cord contusion. Intrathecal administration of noggin – a soluble BMP antagonist—leads to enhanced locomotor activity and reveals significant regrowth of the corticospinal tract after spinal cord contusion. Thus, BMPs play a role in inhibiting axonal regeneration and limiting functional recovery following injury to the CNS.     

Bone morphogenetic proteins in inflammation,glucose homeostasis and adipose tissue energy metabolism

Bore morphogenetic proteins (BMPs) are members of the transforming growth factor (TGF)-β superfamily, a group of secreted proteins that regulate embryonic development. This review summarizes the effects of BMPs on physiological processes not exclusively linked to the musculoskeletal system. Specifically, we focus on the involvement of BMPs in inflammatory disorders, e.g. fibrosis, inflammatory bowel disease, anchylosing spondylitis, rheumatoid arthritis. Moreover, we discuss the role of BMPs in the context of vascular disorders, and explore the role of these signalling proteins in iron homeostasis (anaemia, hemochromatosis) and oxidative damage. The second and third parts of this review focus on BMPs in the development of metabolic pathologies such as type-2 diabetes mellitus and obesity. The pancreatic beta cells are the sole source of the hormone insulin and BMPs have recently been implicated in pancreas development as well as control of adult glucose homeostasis. Lastly, we review the recently recognized role of BMPs in brown adipose tissue formation and their consequences for energy expenditure and adiposity. In summary, BMPs play a pivotal role in metabolism beyond their role in skeletal homeostasis. However, increased understanding of these pleiotropic functions also highlights the necessity of tissue-specific strategies when harnessing BMP action as a therapeutic target.     

Emerging role of bone morphogenetic proteins in angiogenesis

Bone morphogenetic proteins (BMPs) are multifunctional growth factors belonging to the transforming growth factor β (TGFβ) superfamily. Recent observations clearly emphasize the emerging role of BMPs in angiogenesis: (i) two genetic vascular diseases (hereditary hemorrhagic telangiectasia (HHT) and pulmonary arterial hypertension (PAH)) are caused by mutations in genes encoding components of the BMP signalling pathway (endoglin, ALK1 and BMPRII). (ii) BMP9 has been identified as the physiological ligand of the endothelial receptor ALK1 in association with BMPRII. This review will focus on the diverse functions of BMPs in angiogenesis. We will propose a model that distinguishes the BMP2, BMP7 and GDF5 subgroups from the BMP9 subgroup on the basis of their functional implication in the two phases of angiogenesis (activation and maturation).     

Site-specific interaction of bone morphogenetic protein 2 with procollagen II

Bone morphogenetic proteins (BMPs) play a critical role in embryo development, organogenesis, and regeneration of damaged tissues. Biological activity of BMPs depends on their local concentration, which is regulated by intracellular enzymatic processing of pro-BMPs, and then the binding of secreted BMPs to antagonizing extracellular proteins. It has been suggested that BMPs interact with structural proteins of the extracellular matrix, but this process is poorly understood. To study interactions of BMPs with fibrillar collagens in detail we expressed recombinant procollagen II variants in which specific domains that correspond to the D-periods were deleted. Subsequently, the procollagen II variants were used in biosensor and immuno-precipitation binding assays to map the regions of procollagen II with a high affinity for the BMP-2. Our data suggest that interaction of BMP-2 with procollagen II is site-specific, and that the high-affinity binding site is located in the D4-period of the collagen triple helix. We hypothesize that the binding of BMP-2 to collagen II reflects a general mechanism of interaction between the fibrillar collagens and morphogens that belong to the transforming growth factor (TGF)-beta superfamily.     

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.     

Stage-specific effects of bone morphogenetic proteins on the oligodendrocyte lineage

Oligodendrocyte maturation is regulated by multiple secreted factors present in the brain during critical stages of development. Whereas most of these factors promote oligodendrocyte proliferation and survival, members of the bone morphogenetic protein family (BMPs) recently have been shown to inhibit oligodendrocyte differentiation in vitro. Oligodendrocyte precursors treated with BMPs differentiate to the astrocyte lineage. Given that cells at various stages of the oligodendrocyte lineage have distinct responses to growth factors, we hypothesized that the response to BMP would be stage-specific. Using highly purified, stage-specific cultures, we found that BMP has distinct effects on cultured oligodendrocyte preprogenitors, precursors, and mature oligodendrocytes. Oligodendrocyte preprogenitors (PSA-NCAM+, A2B5-) treated with BMP2 or BMP4 developed a novel astrocyte phenotype characterized by a morphological change and expression of glial fibrillary acidic protein (GFAP) but little glutamine synthetase expression and no labeling with A2B5 antibody. In contrast, treating oligodendrocyte precursors with BMPs resulted in the accumulation of cells with the traditional type 2 astrocyte phenotype (GFAP+, A2B5+). However, many of the cells with an astrocytic morphology did not express GFAP or glutamine synthetase unless thyroid hormone was present in the medium. The addition of fibroblast growth factor along with BMP to either oligodendrocyte preprogenitor or the oligodendrocyte precursor cells inhibited the switch to the astrocyte lineage, whereas platelet-derived growth factor addition had no effect. Treatment of mature oligodendrocytes with BMP elicited no change in morphology or expression of GFAP. These data suggest that as cells progress through the oligodendrocyte lineage, they show developmentally restricted responses to the BMPs.     

Regulation by members of the transforming growth factor beta superfamily of the digital and interdigital fates of the autopodial limb mesoderm

Embryonic limb outgrowth is accomplished by the proliferation of mesodermal cells in the progress zone. In this region, mesodermal cells are maintained in an undifferentiated and proliferating state by the action of the apical ectodermal ridge (AER). Differentiation of these cells into individual skeletal elements occurs when the cells are displaced proximally and leave the influence of the AER as a consequence of the accumulation of cells in that region. Here we review the evidence obtained in the last few years showing that members of the transforming growth factor beta (TGFbeta) subfamily and bone morphogenetic proteins (BMPs) act as proximal signals in the autopod regulating the fate of the progress zone cells towards chondrogenesis or apoptosis. Our findings show that apoptosis is regulated by BMPs while chondrogenesis requires the interaction of TGFbetas and BMPs. Fibroblast growth factors (FGFs) produced by the AER exert an opposite function to both TGFbetas and BMPs, maintaining the progress zone cells in an undifferentiated state.     

Stage‐specific effects of bone morphogenetic proteins on the oligodendrocyte lineage

Oligodendrocyte maturation is regulated by multiple secreted factors present in the brain during critical stages of development. Whereas most of these factors promote oligodendrocyte proliferation and survival, members of the bone morphogenetic protein family (BMPs) recently have been shown to inhibit oligodendrocyte differentiation in vitro. Oligodendrocyte precursors treated with BMPs differentiate to the astrocyte lineage. Given that cells at various stages of the oligodendrocyte lineage have distinct responses to growth factors, we hypothesized that the response to BMP would be stage‐specific. Using highly purified, stage‐specific cultures, we found that BMP has distinct effects on cultured oligodendrocyte preprogenitors, precursors, and mature oligodendrocytes. Oligodendrocyte preprogenitors (PSA‐NCAM+, A2B5−) treated with BMP2 or BMP4 developed a novel astrocyte phenotype characterized by a morphological change and expression of glial fibrillary acidic protein (GFAP) but little glutamine synthetase expression and no labeling with A2B5 antibody. In contrast, treating oligodendrocyte precursors with BMPs resulted in the accumulation of cells with the traditional type 2 astrocyte phenotype (GFAP+, A2B5+). However, many of the cells with an astrocytic morphology did not express GFAP or glutamine synthetase unless thyroid hormone was present in the medium. The addition of fibroblast growth factor along with BMP to either oligodendrocyte preprogenitor or the oligodendrocyte precursor cells inhibited the switch to the astrocyte lineage, whereas platelet‐derived growth factor addition had no effect. Treatment of mature oligodendrocytes with BMP elicited no change in morphology or expression of GFAP. These data suggest that as cells progress through the oligodendrocyte lineage, they show developmentally restricted responses to the BMPs. © 2000 John Wiley & Sons, Inc. J Neurobiol 43: 1–17, 2000     

BMPs promote proliferation and migration of endothelial cells via stimulation of VEGF-A/VEGFR2 and angiopoietin-1/Tie2 signalling

The differentiation, growth, and survival of endothelial cells (ECs) are regulated by multiple signalling pathways, such as vascular endothelial growth factors (VEGFs) and angiopoietins through their receptor tyrosine kinases, VEGF receptor (VEGFR) 2 and Tie2, respectively. Bone morphogenetic proteins (BMPs), members of the transforming growth factor (TGF)-beta family, have been implicated in the development and maintenance of vascular systems. However, their effects on EC proliferation remain to be elucidated. In the present study, we show that BMPs induce the proliferation and migration of mouse embryonic stem cell (ESC)-derived endothelial cells (MESECs) and human microvascular endothelial cells (HMECs). Addition of BMP-4 to culture induced significant proliferation and migration of both types of ECs. BMP-4 also increased the expression and phosphorylation of VEGFR2 and Tie2. These findings suggest that BMP signalling activates endothelium via activation of VEGF/VEGFR2 and Angiopoietin/Tie2 signalling.     

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.