Nuclear variants of bone morphogenetic proteins

Background  

Bone morphogenetic proteins (BMPs) contribute to many different aspects of development including mesoderm formation, heart development, neurogenesis, skeletal development, and axis formation. They have previously been recognized only as secreted growth factors, but the present study detected Bmp2, Bmp4, and Gdf5/CDMP1 in the nuclei of cultured cells using immunocytochemistry and immunoblotting of nuclear extracts.     

Bone morphogenetic proteins in vertebrate hematopoietic development

During embryonic development, the hematopoietic system is the first to generate terminally differentiated, functional cell types. The urgent necessity for the early formation of blood and blood vessels during embryogenesis means that the induction, expansion, and maturation of these systems must be rapidly and precisely controlled. Bone morphogenic proteins (BMPs) have been implicated in hematopoietic development in the vertebrate embryo and stimulate the proliferation and/or differentiation of human cord blood hematopoietic stem cells (HSC) and embryonic stem cells in vitro. Here we review the mechanisms of action and potential roles of these soluble signaling molecules in vertebrate hematopoiesis.     

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.     

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).     

Heterodimerization-dependent secretion of bone morphogenetic proteins in Drosophila

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Interaction between coat morphogenetic proteins SafA and SpoVID

Morphogenetic proteins such as SpoVID and SafA govern assembly of the Bacillus subtilis endospore coat by guiding the various protein structural components to the surface of the developing spore. Previously, a screen for peptides able to interact with SpoVID led to the identification of a PYYH motif present in the C-terminal half of the SafA protein and to the subsequent demonstration that SpoVID and SafA directly interact. spoVID and safA spores show deficiencies in coat assembly and are lysozyme susceptible. Both proteins, orthologs of which are found in all Bacillus species, have LysM domains for peptidoglycan binding and localize to the cortex-coat interface. Here, we show that the interaction between SafA and SpoVID involves the PYYH motif (region B) but also a 13-amino-acid region (region A) just downstream of the N-terminal LysM domain of SafA. We show that deletion of region B does not block the interaction of SafA with SpoVID, nor does it bring about spore susceptibility to lysozyme. Nevertheless, it appears to reduce the interaction and affects the complex. In contrast, lesions in region A impaired the interaction of SafA with SpoVID in vitro and, while not affecting the accumulation of SafA in vivo, interfered with the localization of SafA around the developing spore, causing aberrant assembly of the coat and lysozyme sensitivity. A peptide corresponding to region A interacts with SpoVID, suggesting that residues within this region directly contact SpoVID. Since region A is highly conserved among SafA orthologs, this motif may be an important determinant of coat assembly in the group of Bacillus spore formers.     

Bone morphogenetic proteins in destructive and remodeling arthritis

Joint destruction and tissue responses determine the outcome of chronic arthritis. Joint inflammation and damage are often the dominant clinical presentation. However, in some arthritic diseases, in particular the spondyloarthritides, joint remodeling is a prominent feature, with new cartilage and bone formation leading to ankylosis and contributing to loss of function. A role for bone morphogenetic proteins in joint remodeling has been demonstrated in the formation of both enthesophytes and osteophytes. Data from genetic models support a role for bone morphogenetic protein signaling in cartilage homeostasis. Finally, this signaling pathway is likely to play a steering role in the synovium.     

Application of bone morphogenetic proteins in spinal fusion

We are now entering an exciting new era in spinal surgery where the inherent osteoinductive capacity of the body has been harnessed for bone formation for therapeutic purposes. Recombinant bone morphogenetic proteins have been extensively studied in both the pre-clinical and clinical arena for spinal fusion with considerable success. The challenges facing spine surgeons now is the development of site-specific carriers and optimal doses for these growth factors. This review highlights the recent advances in this regard.     

Effects of bone morphogenetic proteins on epithelial repair

Epithelial tissue has important functions such as protection, secretion, and sensation. Epithelial damage is involved in various pathological processes. Bone morphogenetic proteins (BMPs) are a class of growth factors with multiple functions. They play important roles in epithelial cells, including in differentiation, proliferation, and migration during the repair of the epithelium. This article reviews the functions and mechanisms of the most profoundly studied BMPs in the process of epithelial damage repair and their clinical significance.     

Delivering on the promise of bone morphogenetic proteins.

The advent of bone growth factors has been widely anticipated since their successful production using recombinant DNA technology. Bone morphogenetic proteins (BMPs) are an important class of bone growth factors and will be the focus of this article. In the near future these therapeutics might revolutionize how clinicians treat such diverse orthopedic applications as the healing of broken bones, increasing bone density lost through aging, and strengthening the spine. These potent proteins require application directly at the site of repair via a delivery system. The choice of delivery system has a profound effect on the clinical outcome. In the past decade, researchers have focused on developing efficient delivery systems and advancing these factors from the bench to the clinic.     

Expression of bone morphogenetic proteins during membranous bone healing

For the reconstructive plastic surgeon, knowledge of the molecular biology underlying membranous fracture healing is becoming increasingly vital. Understanding the complex patterns of gene expression manifested during the course of membranous fracture repair will be crucial to designing therapies that augment poor fracture healing or that expedite normal osseous repair by strategic manipulation of the normal course of gene expression. In the current study, we present a rat model of membranous bone repair. This model has great utility because of its technical simplicity, reproducibility, and relatively low cost. Furthermore, it is a powerful tool for analysis of the molecular regulation of membranous bone repair by immunolocalization and/or in situ hybridization techniques. In this study, an osteotomy was made within the caudal half of the hemimandible, thus producing a stable bone defect without the need for external or internal fixation. The healing process was then catalogued histologically in 28 Sprague-Dawley rats that were serially killed at 1, 2, 3, 4, 5, 6, and 8 weeks after operation. Furthermore, using this novel model, we analyzed, within the context of membranous bone healing, the temporal and spatial expression patterns of several members of the bone morphogenetic protein (BMP) family, known to be critical regulators of cells of osteoblast lineage. Our data suggest that BMP-2/-4 and BMP-7, also known as osteogenic protein-1 (OP-1), are expressed by osteoblasts, osteoclasts, and other more primitive mesenchymal cells within the fracture callus during the early stages of membranous fracture healing. These proteins continue to be expressed during the process of bone remodeling, albeit less prominently. The return of BMP-2/-4 and OP-1 immunostaining to baseline intensity coincides with the histological appearance of mature lamellar bone. Taken together, these data underscore the potentially important regulatory role played by the bone morphogenetic proteins in the process of membranous bone repair.     

骨形成蛋白调控成骨分化的信号机制

骨形成蛋白(bone morphogenetic proteins,BMPs)能诱导成骨细胞和软骨细胞的分化成熟,并能在体内诱导异位成骨。BMPs与骨形成蛋白受体BMPR结合,通过Smads和p38MAPKs途径进行信号转导,并通过下游转录因子Cbfal、Osterix、Dlx等与相应的成骨细胞特异蛋白碱性磷酸酶、骨钙素、OPN等基因启动子连接,促进细胞向成骨方向分化。另外,还通过转录因子CIZ、AJ18等对成骨进行负调控,维持胚胎发育正常,保持骨量平衡。由于BMPs在骨修复中的重要作用,现已成为基因治疗用于骨缺损的一个研究热点。     

Bone grafts and bone morphogenetic proteins in spine fusion

Spinal fusions are being performed for various pathologies of the spine. Stabilizing vertebral segments by eliminating motion across those segments becomes critical in dealing with pathologies of the spine that lead to instability. The use of autograft has been the gold standard for spine fusion. However, due to complications such as donor site morbidity, increased operating time, and limited supply, the use of allograft as a graft extender has become an acceptable practice especially in fusions spanning multiple segments. The discovery and isolation of novel proteins (i.e., bone morphogenetic proteins, BMPs), which initiate the molecular cascade of bone formation, have experimentally been shown in numerous animal studies to be as effective as autografts. Although the use of BMPs has exciting applications in spine surgery, long-term clinical studies must be evaluated for its efficacy in various applications in humans. The use of biomimetic materials such as hydroxyapatite (HA), or tricalcium phosphate (TCP) has also been examined in several animal models as bone graft substitutes or carriers. Although these materials have shown some promise in specific site applications, more work remains in elucidating an efficacious combination of these materials and BMPs that can be as effective as autografts. This review will present the status of bone grafts, bone morphogenetic proteins, gene therapy, and work that has been done to facilitate spinal fusion and simultaneously eliminate the need for bone graft. This revised version was published online in July 2006 with corrections to the Cover Date.     

Delivery of bone morphogenetic proteins for orthopedic tissue regeneration

Carriers for bone morphogenetic proteins (BMPs) are used to increase retention of these factors at orthopedic treatment sites for a sufficient period of time to allow regenerative tissue forming cells to migrate to the area of injury and to proliferate and differentiate. Carriers can also serve as a matrix for cell infiltration while maintaining the volume in which repair tissue can form. Carriers have to be biocompatible and are often required to be bioresorbable. Carriers also have to be easily, and cost-effectively, manufactured for large-scale production, conveniently sterilized and have appropriate storage requirements and stability. All of these processes have to be approvable by regulatory agencies. The four major categories of BMP carrier materials include natural polymers, inorganic materials, synthetic polymers, composites of these materials. Autograft or allograft carriers have also used. Carrier configurations range from simple depot delivery systems to more complex systems mimicking the extracellular matrix structure and function. Bone regenerative carriers include depot delivery systems for fracture repair, three-dimensional polymer or ceramic composites for segmental repairs and spine fusion and metal or metal/ceramic composites for augmenting implant integration. Tendon/ligament regenerative carriers range from depot delivery systems to three-dimensional carriers that are either randomly oriented or linearly oriented to improve regenerative tissue alignment. Cartilage regenerative systems generally require three-dimensional matrices and often incorporate cells in addition to factors to augment the repair. Alternative BMP delivery systems include viral vectors, genetically altered cells, conjugated factors and small molecules.     

The signaling and functions of heterodimeric bone morphogenetic proteins

Heterodimeric bone morphogenetic proteins (BMPs) consist of disulfide-linked dimeric monomers derived from different BMP members. Owing to this specific constitution pattern, they bear high affinity to both type I and type II BMP receptors simultaneously. Meanwhile, the antagonism efficiency of extracellular antagonists to heterodimeric BMPs is also significantly lower than that to homodimeric ones. All these specific properties confer heterodimeric BMPs with distinct signaling and bio-functions that are characterized by more speediness, lower concentration/dose threshold and higher efficiency than homodimeric BMPs. Consequently, heterodimeric BMPs bear promising application potential in inducing osteogenesis. In addition, they may play indispensible roles in organogenesis. In this review, we summarize the current knowledge of heterodimeric BMPs in their signaling pathways and bio-functions.     

Bone morphogenetic proteins in development and homeostasis of kidney

Bone morphogenetic proteins play a key role in kidney development and postnatal function. The kidney has been identified as a major site of bone morphogenetic protein (BMP)-7 synthesis during embryonic and postnatal development, which mediates differentiation and maintenance of metanephric mesenchyme. Targeted disruption of BMP-7 gene expression in mice resulted in dysgenic kidneys with hydroureters, causing uremia within 24h after birth. Several experimental animal models of acute and chronic renal injury have all unequivocally shown beneficial effect of BMP-7 in ameliorating the severity of damage by preventing inflammation and fibrosis. Apart from the beneficial effect on kidney disease itself, BMP-7 improves important complications of chronic renal impairment such as renal osteodystrophy and vascular calcification.