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Bone Morphogenetic Proteins in Craniofacial Surgery: Current Techniques, Clinical Experiences, and the Future of Personalized Stem Cell Therapy
Kristofer E. Chenard,Chad M. Teven,Tong-Chuan He,Russell R. Reid
Journal of Biomedicine and Biotechnology , 2012, DOI: 10.1155/2012/601549
Abstract: Critical-size osseous defects cannot heal without surgical intervention and can pose a significant challenge to craniofacial reconstruction. Autologous bone grafting is the gold standard for repair but is limited by a donor site morbidity and a potentially inadequate supply of autologous bone. Alternatives to autologous bone grafting include the use of alloplastic and allogenic materials, mesenchymal stem cells, and bone morphogenetic proteins. Bone morphogenetic proteins (BMPs) are essential mediators of bone formation involved in the regulation of differentiation of osteoprogenitor cells into osteoblasts. Here we focus on the use of BMPs in experimental models of craniofacial surgery and clinical applications of BMPs in the reconstruction of the cranial vault, palate, and mandible and suggest a model for the use of BMPs in personalized stem cell therapies.
The Use of Platelet Rich Plasma, Bone Morphogenetic Protein-2 and Different Scaffolds in Oral and Maxillofacial Surgery - Literature Review in Comparison with Own Clinical Experience  [cached]
Karl-Heinz Schuckert,Stefan Jopp,Magdalena Osadnik
Journal of Oral & Maxillofacial Research , 2011,
Abstract: Objectives: The purpose of this article was to review and critically assess the use of platelet rich plasma, recombinant human bone morphogenetic protein-2 and different scaffolds (i.e. tricalciumphosphate, polycaprolactone, demineralized bone matrix and anorganic bovine bone mineral) in oral and maxillofacial surgery comparing the relevant literature and own clinical experience.Material and Methods: A literature review was conducted using MEDLINE, MEDPILOT and COCHRANE DATABASE OF SYSTEMATIC REVIEWS. It concentrated on manuscripts and overviews published in the last five years (2006-2010). The key terms employed were platelet rich plasma, bone morphogenetic proteins and their combinations with the above mentioned scaffolds. The results of clinical studies and animal trials were especially emphasized. The statements from the literature were compared with authors’ own clinical data.Results: New publications and overviews demonstrate the advantages of platelet rich plasma in bone regeneration. The results from the literature review were discussed and compared with the publications detailing authors’ own experiences.Conclusions: A favourable outcome concerning newly grown bone was achieved combining platelet rich plasma in addition to optimal matrices with or without recombinant human bone morphogenetic protein-2, depending on the clinical case. As a consequence, the paradigm shift from transplantation of autogenous bone to bone tissue engineering appears promising.
Association between expression of the Bone morphogenetic proteins 2 and 7 in the repair of circumscribed cartilage lesions with clinical outcome
Hagen Schmal, Philipp Niemeyer, J?rn Zwingmann, Fabian Stoffel, Norbert P Südkamp, Alexander T Mehlhorn
BMC Musculoskeletal Disorders , 2010, DOI: 10.1186/1471-2474-11-170
Abstract: Lavage fluids of knee joints of 47 patients were collected during surgical therapy. 5 patients had no cartilage lesion and served as a control group, the other 42 patients with circumscribed cartilage defects were treated by microfracturing (19) or by an Autologous Chondrocyte Implantation (23). The concentrations of BMP-2 and BMP-7 were determined by ELISA. The clinical status was evaluated using the IKDC Score prior to and 1 year following the operation.High level expression in the control group was found for BMP-2, concentrations of BMP-7 remained below detection levels. No statistical differences could be detected in concentrations of BMP-2 or BMP-7 in the lavage fluids of knees with cartilage lesions compared to the control group. Levels of BMP-7 did not change after surgical cartilage repair, whereas concentrations of BMP-2 statistically significant increased after the intervention (p < 0.001). The clinical outcome following cartilage regenerating surgery increased after 1 year by 29% (p < 0.001). The difference of the IKDC score after 1 year and prior to the operation was used to quantify the degree of improvement following surgery. This difference statistically significant correlated with initial BMP-2 (R = 0.554, p < 0.001) but not BMP-7 (R = 0.031, n.s.) levels in the knee joints.BMP-2 seems to play an important role in surgically induced cartilage repair; synovial expression correlates with the clinical outcome.Circumscribed cartilage defects are considered as an initial event in the progress of osteoarthritis (OA) [1]. In the last decades different methods have been developed for treatment of this pathology. The Autologous Chondrocyte Implantation (ACI) and microfracturing are regarded as established procedures with documented success in prevention of OA-development. Despite clinical improvement one-third of the patients show early radiographic signs of OA five years after surgery independent from used kind of surgical management [2]; this indicates a ce
Development and application of bone morphogenetic proteins for the enhancement of bone healing
C. A. Kirker-Head
Journal of Orthopaedics and Traumatology , 2005, DOI: 10.1007/s10195-005-0072-y
Abstract: Bone morphogenetic proteins are multifunctional cytokines and members of the transforming growth factor-β superfamily. They include the only signaling molecules that can singly induce de novo bone formation at orthotopic and heterotopic sites. Their osteoinductive potency and ability to enhance or accelerate bone healing has been demonstrated in animal models of human orthopedic injuries and diseases, and in human clinical orthopedic patients. Recombinant human bone morphogenetic proteins 2 and 7 have recently received the approval of regulatory agencies for the clinical treatment of selected human acute long bone fractures and nonunions, as well as lumbar fusion. It is likely that additional indications will be approved as supportive data for the proteins’ efficacy in the treatment of specific orthopedic conditions are generated. In addition to the type I collagen presently being used clinically as a locally implantable delivery vehicle for bone morphogenetic proteins, mineral, synthetic polymer, and extracellular matrix components continue to be tested as alternative matrices. Other means of bone morphogenetic protein delivery undergoing preliminary evaluation include gene transfer therapy and systemic administration.
Bases teóricas y aplicación clínica de las proteínas morfogenéticas óseas en cirugía maxilofacial Base theories and the clinical application of bone morphogenetic proteins in maxillofacial surgery  [cached]
C.M. Ardila Medina
Revista Espa?ola de Cirugía Oral y Maxilofacial , 2009,
Abstract: Uno de los grandes avances en la neoformación ósea ha sido la identificación de factores de crecimiento importantes para ella como son las proteinas morfogenéticas óseas (PMO) que regulan la diferenciación ósea y cartilaginosa in vivo. La depuración, clonación genética y expresión de las PMO han establecido las bases para el análisis celular y molecular del desarrollo y la regeneración ósea. El estudio genético de las PMO se ala que son esenciales para la función normal animal y en la osteogénesis postfetal es importante en el desarrollo embrionario orgánico, esquelético y de los tejidos dentales y craneofaciales. La disponibilidad de las PMO proporciona retos y oportunidades para mejorar los conocimientos que regulan la regeneración ósea con el fin de optimizar los resultados en el paciente. One of the fundamental advances in bone neoformation has been the identification of important growth factors like the bone morphogenetic proteins that regulate live cartilage and bone differentiation. The cleansing, genetic cloning and expression of recombinant human bone morphogenetic proteins (BMP) have laid the basis for cellular and molecular analysis of bone development and regeneration. The genetic study of the BMPs indicates that they are essential to the normal development and function of animals. BMP post-natal bone development is also very important in embryonic organic, skeletal, craniofacial and dental tissue development. The availability of BMPs provides several challenges and opportunities to improve insights into the mechanisms that regulate the regeneration of bone for optimal outcome in the patient.
Nuclear variants of bone morphogenetic proteins
Jenny E Felin, Jaime L Mayo, Trina J Loos, J Daniel Jensen, Daniel K Sperry, Stephanie L Gaufin, Christopher A Meinhart, Jennie B Moss, Laura C Bridgewater
BMC Cell Biology , 2010, DOI: 10.1186/1471-2121-11-20
Abstract: In all three proteins, a bipartite nuclear localization signal (NLS) was found to overlap the site at which the proproteins are cleaved to release the mature growth factors from the propeptides. Mutational analyses indicated that the nuclear variants of these three proteins are produced by initiating translation from downstream alternative start codons. The resulting proteins lack N-terminal signal peptides and are therefore translated in the cytoplasm rather than the endoplasmic reticulum, thus avoiding proteolytic processing in the secretory pathway. Instead, the uncleaved proteins (designated nBmp2, nBmp4, and nGdf5) containing the intact NLSs are translocated to the nucleus. Immunostaining of endogenous nBmp2 in cultured cells demonstrated that the amount of nBmp2 as well as its nuclear/cytoplasmic distribution differs between cells that are in M-phase versus other phases of the cell cycle.The observation that nBmp2 localization varies throughout the cell cycle, as well as the conservation of a nuclear localization mechanism among three different BMP family members, suggests that these novel nuclear variants of BMP family proteins play an important functional role in the cell.Bone morphogenetic proteins (BMPs) were first identified nearly 20 years ago as components of a protein extract derived from bone that could direct cartilage and bone formation [1,2]. The BMPs have since been shown to play roles in multiple other developmental pathways [3,4]. For example, Bmp2 provides positional information during axis formation and limb patterning [5,6]. It is expressed in interdigital mesenchyme where apoptosis is occurring, and it induces apoptosis in human myeloma cells [7,8]. In contrast, Bmp2 prevents apoptosis in a chondrocytic cell line and in breast cancer cells [9,10]. In the embryonic lethal Bmp2 null mouse, amnion/chorion development is compromised and the heart is malformed [11,12]. Bmp2 is required for neural crest cell migration, and it promotes neuronal dif
Bone morphogenetic proteins and growth factors: emerging role in regenerative orthopaedic surgery*
P. De Biase,R. Capanna
Journal of Orthopaedics and Traumatology , 2007, DOI: 10.1007/s10195-007-0162-0
Abstract: Bone morphogenetic proteins (BMPs) were discovered by Urist and colleagues in 1965 and later defined as multifunctional cytokines involved in osteoinduction. BMPs are members of the transforming growth factor-β superfamily, with the exception of the BMP-1. Presently, at least 20 BMPs have been identified and studied, but only BMP 2, 4 and 7 have been able in vitro to stimulate the entire process of stem cell differentiation into osteoblastic mature cells. In preclinical and clinical studies, BMPs have demonstrated potential in osteoinduction and have been approved for clinical use in treating open fractures of the long bones and nonunions and in vertebral arthrodesis. Additional clinical uses of these molecules are under investigation and the possibility of using gene therapy in selected pathologies seems the most appealing.
Regulation of oligodendrocyte progenitor cell maturation by PPARδ: effects on bone morphogenetic proteins  [cached]
Maria Vittoria Simonini,Paul E Polak,Anne I Boullerne,Jeffrey M Peters
ASN Neuro , 2010, DOI: 10.1042/an20090033
Abstract: In EAE (experimental autoimmune encephalomyelitis), agonists of PPARs (peroxisome proliferator-activated receptors) provide clinical benefit and reduce damage. In contrast with PPARγ, agonists of PPARδ are more effective when given at later stages of EAE and increase myelin gene expression, suggesting effects on OL (oligodendrocyte) maturation. In the present study we examined effects of the PPARδ agonist GW0742 on OPCs (OL progenitor cells), and tested whether the effects involve modulation of BMPs (bone morphogenetic proteins). We show that effects of GW0742 are mediated through PPARδ since no amelioration of EAE clinical scores was observed in PPARδ-null mice. In OPCs derived from E13 mice (where E is embryonic day), GW0742, but not the PPARγ agonist pioglitazone, increased the number of myelin-producing OLs. This was due to activation of PPARδ since process formation was reduced in PPARδ-null compared with wild-type OPCs. In both OPCs and enriched astrocyte cultures, GW0742 increased noggin protein expression; however, noggin mRNA was only increased in astrocytes. In contrast, GW0742 reduced BMP2 and BMP4 mRNA levels in OPCs, with lesser effects in astrocytes. These findings demonstrate that PPARδ plays a role in OPC maturation, mediated, in part, by regulation of BMP and BMP antagonists.
Bone morphogenetic proteins in destructive and remodeling arthritis
Rik JU Lories, Frank P Luyten
Arthritis Research & Therapy , 2007, DOI: 10.1186/ar2135
Abstract: The classic signs and symptoms of arthritis – rubor, tumor, calor, dolor et functio laesa – cover a vast world of dynamic systemic and local processes with complex interactions between networks at the cellular and molecular levels. Major advances in our understanding of the pathology of chronic arthritis and new imaging techniques have highlighted distinct mechanisms of disease. In the joint, these include the development and persistence of an inflammatory and immune reaction, the activation of tissue destructive enzymes and cells, and the suppression or stimulation of molecular pathways regulating homeostasis, repair and remodeling (Figure 1).Mechanisms of inflammation and auto-immunity have been studied most extensively, leading to the identification of key cell populations, such as T cells, B cells and macrophages, and of important messenger molecules, including cytokines such as tumor necrosis factor-α (TNFα). As a result, innovative targeted therapeutic strategies have an unprecedented effect on both rheumatoid arthritis (RA) and the spondyloarthritides (SpA). In addition, new immunological targets are identified at an amazing pace [1].Two discoveries have recently opened up new paths of investigation for cartilage and bone destruction: the molecular characterization of osteoclast differentiation and activation [2] and the transformation of the synovium into tissue-destructive pannus tissue [3]. In addition, the success of the current treatment strategies has prompted new attention to be focused on repair and remodeling responses of joint tissues [4].Tissue responses to inflammation or destruction in the joint can be physiological or pathological. Normal tissue responses include the regeneration or repair of soft and hard tissues, including cartilage and bone. Tissue regeneration involves a complete restoration of the original tissue with maintenance of function and homeostasis. This is perceived as a rare event. In tissue repair, the damaged tissue is replaced
Interplay between bone morphogenetic proteins and cognate binding proteins in bone and cartilage development: noggin, chordin and DAN
Hari A Reddi
Arthritis Research & Therapy , 2000, DOI: 10.1186/ar133
Abstract: The sequelae of damage and degradation of articular cartilage is well known in osteoarthritis. Repair and regeneration of articular cartilage in experimental animals is initiated when the subchondral bone is penetrated, as in full thickness defects. On the other hand, there is no repair in partial thickness defects with the defect confined to cartilage only. Subchondral bone with associated matrix and hematopoietic stromal cells may thus play a role in cartilage repair. The difference in regenerative potential between bone and cartilage is immense. The fundamental differences between cartilage and bone in inherent repair potential may be due to differences in concentration of endogeneous growth and morphogenetic factors and their antagonists. The demineralized bone matrix is a repository of BMPs and this might explain, in part, the repair of articular cartilage in full thickness defects. The aim of this commentary is to discuss the interplay between the evolving family of BMPs and cognate BMP binding proteins in bone and cartilage development. In arthritis, with attendant cartilage damage, there is a derangement of the morphogenetic signals. It is thus possible to harness the recent progress in developmental biology of morphogens to design rational therapeutic approaches to cartilage regeneration. Regeneration is, after all, a recapitulation of embryonic development and morphogenesis, and includes redeployment of morphogens in regeneration.BMPs are a family of growth and differentiation factors [1,2]. BMPs are pleiotropic morphogens, and they induce new cartilage and bone formation in ectopic sites by a developmental sequence that mimics limb development and morphogenesis. BMPs have chemotactic, mitogenic and differentiation-inducing properties. The actions of BMPs are concentration dependent, and are based on thresholds. BMPs are dimeric proteins with a single interchain disulfide bond. The dimeric conformation is an absolute requirement for the biological action a
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