Cytokine & Growth Factor Reviews RSS feed: Current Issue. Cytokine & Growth Factor Reviews publishes thought-provoking articles (critical reviews, state-of-the-art reviews, letters to the editor, meeting reviews) devoted to important advances in the rapidly changing fields of growth factor and cytokine research. Major emphasis is placed on the multidisciplinary significance of cytokines and growth factors in areas as diverse as signal transduction, cell growth and differentiation, embryonic development, immunology, tumorigenesis and clinical medicine.http://www.cgfr.co.uk/?rss=yesElsevier Inc.en © 2009 Published by Elsevier Inc. All rights reserved. Cytokine & Growth Factor Reviews1359-6101205-6October 2009 © 2009 Published by Elsevier Inc. All rights reserved. healthpermissions@elsevier.comhttp://www.cgfr.co.uk/article/PIIS1359610109000999/abstract?rss=yesEditorial Board10.1016/S1359-6101(09)00099-9Cytokine & Growth Factor Reviews 20, 5 (2009)2009-10-01Cytokine & Growth Factor Reviews2009-10-01205-6S1359-6101(09)X0006-7CO2CO2http://www.cgfr.co.uk/article/PIIS1359610109000902/abstract?rss=yesAmong the many tissues in the human body bone has the highest potential for regeneration. What is the molecular basis of this regenerative prowess in bones? Bone is composed of an organic matrix that is principally collagenous and is mineralized with inorganic crystals of hydroxyapatite. Demineralization of the bone results in a demineralized bone matrix. The demineralized bone matrix is a bioactive, biodegradable, biomaterial that induces bone morphogenesis in the extraskeletal ectopic sites. The bioactive signal is bone morphogenetic protein (BMP). There are twenty genes in the human genome that encode functional BMPs . Bone morphogenesis is a sequential multistep biological chain reaction and the key steps are chemotaxis of progenitors/stem cells, proliferation of cells and differentiation of true endochondral bone formation. It is well known that regeneration is in part recapitulation of embryonic development and therefore it is not surprising that recombinant BMPs 2 and 7 are currently approved by the Food and Drug Administration (FDA) for spine fusion, fracture healing and oral surgery . This is indeed remarkable that recombinant morphogens BMPs are in everyday clinical use all over the world.Bone morphogenetic proteins (BMPs): From morphogens to metabologensA. Hari Reddi, Anand Reddi10.1016/j.cytogfr.2009.10.015Cytokine & Growth Factor Reviews 20, 5 (2009)2009-11-09Cytokine & Growth Factor Reviews2009-11-09205-6S1359-6101(09)X0006-7341342http://www.cgfr.co.uk/article/PIIS1359610109000823/abstract?rss=yesAbstract: Bone Morphogenetic Proteins (BMPs) play an important role during organ development and during regeneration after tissue damage. BMPs signal via transmembrane serine/threonine kinase receptors. From our current understanding heteromeric complexes of type I and type II receptors are required for signal propagation. Presently, three type I and three type II receptors are known to bind BMPs with different affinities. Ligands and receptors eventually oligomerize via defined modes into signaling complexes. Co-receptors recruit into these complexes to either inhibit or to promote signaling. The Smad pathway, initiated by phosphorylation through the activated type I receptors, results in transcriptional regulation of early target genes. However, on its way to the nucleus, Smads represent signaling platforms for other pathways, which eventually finetune BMP signal transduction. We also describe BMP-induced signaling cascades leading to cytoskeletal rearrangements, non-transcriptional and non-Smad pathways. BMPs induce a plethora of different cellular effects ranging from stem cell maintenance, migration, differentiation, proliferation to apoptosis. The molecular mechanism, by which the same ligand induces these manifold effects, depends on the cellular context. Here we try to give a current picture of the most important players in regulating and directing BMP signaling towards the desired cellular outcome. Examples of BMP action during development, but also physiological and pathophysiological conditions in the adult organism are presented.Recent advances in BMP receptor signalingChristina Sieber, Jessica Kopf, Christian Hiepen, Petra Knaus10.1016/j.cytogfr.2009.10.007Cytokine & Growth Factor Reviews 20, 5 (2009)2009-11-09Cytokine & Growth Factor Reviews2009-11-09205-6S1359-6101(09)X0006-7343355http://www.cgfr.co.uk/article/PIIS1359610109000926/abstract?rss=yesAbstract: BMPs pattern the dorsal–ventral axis of vertebrate embryos. Smad1/5/8 transduces the BMP signal, and receives phosphorylation inputs from both MAPK and GSK3. Phosphorylation of Smad1 by MAPK and GSK3 result in its polyubiquitination and transport to the centrosome where it is degraded by the proteasome. These linker phosphorylations inhibit BMP/Smad1signaling by shortening its duration. Wnt, which negatively regulates GSK3 activity, prolongs the BMP/Smad1 signal. Remarkably, linker-phosphorylated Smad1 has been shown to be inherited asymmetrically during cell division. Drosophila contains a single Smad1/5/8 homologue, Mad, and is stabilized by phosphorylation-resistant mutations at GSK3 sites, causing Wingless-like effects. We summarize here the significance of linker-phosphorylated Smad1/Mad in relation to signal intensity and duration, and how this integrates the Wnt and BMP pathways during cell differentiation.Integration of BMP and Wnt signaling via vertebrate Smad1/5/8 and Drosophila MadEdward Eivers, Hadrien Demagny, E.M. De Robertis10.1016/j.cytogfr.2009.10.017Cytokine & Growth Factor Reviews 20, 5 (2009)2009-11-06Cytokine & Growth Factor Reviews2009-11-06205-6S1359-6101(09)X0006-7357365http://www.cgfr.co.uk/article/PIIS1359610109000975/abstract?rss=yesAbstract: The TGF-β superfamily exhibits a feature making it distinct from many other growth factor families in that the inadequate number of ligands and receptors premises a high degree of promiscuity in ligand–receptor interaction. This highlights the importance of even small differences in affinities and specificities between different binding partners to maintain the broad spectrum of their well defined biological functions. Despite the promiscuous interactions recent data reveal differences in receptor recruitment, architectures of these assemblies and specific modulation by a multitude of extracellular as well as membrane-associated factors. These modulatory mechanisms might possibly add specificity towards defined biological functions despite the overlapping usage of receptors by various ligands.Intricacies of BMP receptor assemblyJoachim Nickel, Walter Sebald, Jay C. Groppe, Thomas D. Mueller10.1016/j.cytogfr.2009.10.022Cytokine & Growth Factor Reviews 20, 5 (2009)2009-11-18Cytokine & Growth Factor Reviews2009-11-18205-6S1359-6101(09)X0006-7367377http://www.cgfr.co.uk/article/PIIS1359610109000859/abstract?rss=yesAbstract: Smad proteins are intracellular molecules that mediate the canonical signaling cascade of TGFβ superfamily growth factors. The TGFβ superfamily comprises two groups of growth factors, BMPs and TGFβs. Both groups can be further divided into several sub-groups based on sequence homologies and functional similarities. Ligands of the TGFβ superfamily bind to cell surface receptors to activate Smad proteins in the cytoplasm; then the activated Smad proteins translocate into the nucleus to activate or repress specific target gene transcription. Both groups of growth factors play important roles in skeletal development and regeneration. However, whether these effects reflect signaling through canonical Smad pathways, or other non-canonical signaling pathways in vivo remains a mystery. Moreover, the mechanisms utilized by Smad proteins to initiate nuclear events and their interactions with cytoplasmic proteins are still under intensive investigation. This review will discuss the most recent progress understanding Smad signaling in the context of skeletal development and regeneration.Smad signaling in skeletal development and regenerationBuer Song, Kristine D. Estrada, Karen M. Lyons10.1016/j.cytogfr.2009.10.010Cytokine & Growth Factor Reviews 20, 5 (2009)2009-11-20Cytokine & Growth Factor Reviews2009-11-20205-6S1359-6101(09)X0006-7379388http://www.cgfr.co.uk/article/PIIS1359610109000835/abstract?rss=yesAbstract: The BMP signaling pathway controls a number of cell processes during development and in adult tissues. At the cellular level, ligands of the BMP family act by binding a hetero-tetrameric signaling complex, composed of two type I and two type II receptors. BMP ligands make use of a limited number of receptors, which in turn activate a common signal transduction cascade at the intracellular level. A complex regulatory network is required in order to activate the signaling cascade at proper times and locations, and to generate specific downstream effects in the appropriate cellular context.One such regulatory mechanism is the repulsive guidance molecule (RGM) family of BMP co-receptors. This article reviews the current knowledge regarding the structure, regulation, and function of RGMs, focusing on known and potential roles of RGMs in physiology and pathophysiology.The RGM/DRAGON family of BMP co-receptorsElena Corradini, Jodie L. Babitt, Herbert Y. Lin10.1016/j.cytogfr.2009.10.008Cytokine & Growth Factor Reviews 20, 5 (2009)2009-11-09Cytokine & Growth Factor Reviews2009-11-09205-6S1359-6101(09)X0006-7389398http://www.cgfr.co.uk/article/PIIS1359610109000811/abstract?rss=yesAbstract: The ability of mature organisms to stabilize phenotypes has enormous selective advantage across all phyla, but the mechanisms have been largely unexplored. Individuals with fibrodysplasia ossificans progressiva (FOP), a rare genetic disorder of progressive heterotopic ossification, undergo a pathological metamorphosis in which one normal tissue is transformed into another through a highly regulated process of tissue destruction and phenotype reassignment. This disabling metamorphosis is mediated by the FOP metamorphogene, which encodes a mutant bone morphogenetic protein (BMP) type I receptor that exhibits mild constitutive activity during development and severe episodic dysregulation postnatally. The discovery of the FOP metamorphogene reveals a highly conserved target for drug development and identifies a fundamental defect in the BMP signaling pathway that when triggered by injury and inflammation transforms one tissue into another.The FOP metamorphogene encodes a novel type I receptor that dysregulates BMP signalingFrederick S. Kaplan, Robert J. Pignolo, Eileen M. Shore10.1016/j.cytogfr.2009.10.006Cytokine & Growth Factor Reviews 20, 5 (2009)2009-11-09Cytokine & Growth Factor Reviews2009-11-09205-6S1359-6101(09)X0006-7399407http://www.cgfr.co.uk/article/PIIS1359610109000963/abstract?rss=yesAbstract: Bone morphogenetic proteins (BMPs) provide critical signals for determining cell fate, specifying gastrulation, embryonic patterning, organogenesis, and the remodeling of diverse tissues. Recent work has suggested that in addition to coordinating pivotal events in development, BMPs may also regulate certain homeostatic physiological processes independently of effects on cell growth or differentiation. We recently described the identification of dorsomorphin, a small molecule inhibitor of BMP type I receptors which inhibits BMP signaling in preference to TGF-β, Activin, and other ligands of the TGF-β family. We describe a number of strategies using dorsomorphin and its derivatives as probes to assess the physiologic roles of BMP signaling. We also discuss several potential applications for small molecule BMP inhibitors, including stem cell manipulation, and the therapeutic modification of bone remodeling, heterotopic ossification, and iron homeostasis.Applications of small molecule BMP inhibitors in physiology and diseaseCharles C. Hong, Paul B. Yu10.1016/j.cytogfr.2009.10.021Cytokine & Growth Factor Reviews 20, 5 (2009)2009-11-18Cytokine & Growth Factor Reviews2009-11-18205-6S1359-6101(09)X0006-7409418http://www.cgfr.co.uk/article/PIIS135961010900077X/abstract?rss=yesAbstract: Mesenchymal stem cells (MSCs) have been described as being able to give rise to several quite different mesenchymal cell phenotypes. However, the ability to differentiate is not the only characteristic that makes these cells attractive for therapeutic purposes. The secretion of a broad range of bioactive molecules by MSCs, such as growth factors, cytokines and chemokines, constitutes their most biologically significant role under injury conditions. Understanding this intricate secretory activity as well as the properties of MSCs in vivo is central to harnessing their clinical potential. Herein, we identify some of the molecules involved in the paracrine effects of MSCs with a perspective that these cells intrinsically belong to a perivascular niche in vivo, and discuss how this knowledge could be advantageously used in clinical applications.Mechanisms involved in the therapeutic properties of mesenchymal stem cellsLindolfo da Silva Meirelles, Aparecida Maria Fontes, Dimas Tadeu Covas, Arnold I. Caplan10.1016/j.cytogfr.2009.10.002Cytokine & Growth Factor Reviews 20, 5 (2009)2009-11-20Cytokine & Growth Factor Reviews2009-11-20205-6S1359-6101(09)X0006-7419427http://www.cgfr.co.uk/article/PIIS1359610109000896/abstract?rss=yesAbstract: Multi-lineage progenitors, e.g. mesenchymal stem cells, persist in adult developed organs, making a windfall for the cell therapist but an enigma for stem cell biologists. Recent results from our own and other laboratories show that the ancestor of these elusive adult stem cells is likely to be found in the perivascular area, explaining the ubiquitous distribution of these cells in the body. We have prospectively identified and purified vascular pericytes in multiple human organs and shown that these cells are potent mesodermal progenitors that give rise to genuine mesenchymal stem cells in culture. Pericytes can differentiate into diverse cell lineages, but also secrete multiple paracrine growth factors/cytokines, which likely explains in part their robust regenerative potential.Perivascular multi-lineage progenitor cells in human organs: Regenerative units, cytokine sources or both?Chien-Wen Chen, Elisa Montelatici, Mihaela Crisan, Mirko Corselli, Johnny Huard, Lorenza Lazzari, Bruno Péault10.1016/j.cytogfr.2009.10.014Cytokine & Growth Factor Reviews 20, 5 (2009)2009-11-18Cytokine & Growth Factor Reviews2009-11-18205-6S1359-6101(09)X0006-7429434http://www.cgfr.co.uk/article/PIIS1359610109000872/abstract?rss=yesAbstract: Dental caries is a common public health problem, causing early loss of dental pulp and resultant tooth loss. Dental pulp has important functions to sustain teeth providing nutrient and oxygen supply, innervation, reactionary/reparative dentin formation and immune response. Regeneration of pulp is an unmet need in endodontic therapy, and angiogenesis/vasculogenesis and neurogenesis are critical for pulp regeneration. Permanent and deciduous pulp tissue is easily available from teeth after extraction without ethical issues and has potential for clinical use. In this review, we introduce some stem cell subfractions, CD31−/CD146− SP cells and CD105+ cells with high angiogenic and neurogenic potential, derived from human adult dental pulp tissue. Potential utility of these cells is addressed as a source of cells for treatment of cerebral and limb ischemia and pulp inflammation complete with angiogenesis and vasculogenesis.Human dental pulp stem cells with highly angiogenic and neurogenic potential for possible use in pulp regenerationMisako Nakashima, Koichiro Iohara, Masahiko Sugiyama10.1016/j.cytogfr.2009.10.012Cytokine & Growth Factor Reviews 20, 5 (2009)2009-11-09Cytokine & Growth Factor Reviews2009-11-09205-6S1359-6101(09)X0006-7435440http://www.cgfr.co.uk/article/PIIS1359610109000951/abstract?rss=yesAbstract: Bone morphogenetic protein-6 (BMP-6) is produced by bone marrow-mesenchymal (BMSC) and hematopoietic stem cells, which can differentiate into bone, cartilage, adipose, muscle, hematopoietic, synovial and other tissues. Bmp6−/− null mice have low hepcidin serum levels and an iron overload, resembling hereditary hemochromatosis, which may cause a reduced number of pancreatic β-cells, increased serum glucose and diabetes. BMP-6 circulates in the normal human plasma and is produced by BMSC prior to differentiation into osteoblasts. Moreover, it is also released by osteoclasts as a key bone coupling factor recruiting osteoblasts to the resorption site. Due to unique structural, receptor binding and signaling characteristics much smaller amounts of BMP-6 than BMP-7 are needed in vivo to induce regeneration of bone defects in animals.BMP-6 and mesenchymal stem cell differentiationSlobodan Vukicevic, Lovorka Grgurevic10.1016/j.cytogfr.2009.10.020Cytokine & Growth Factor Reviews 20, 5 (2009)2009-11-09Cytokine & Growth Factor Reviews2009-11-09205-6S1359-6101(09)X0006-7441448http://www.cgfr.co.uk/article/PIIS135961010900080X/abstract?rss=yesAbstract: Ligands of the Transforming Growth Factor type β (TGFβ) family exert multiple and sometimes opposite effects on most cell types in vivo depending on cellular context, which mainly includes the stage of the target cell, the local environment of this cell or niche, and the identity and the dosage of the ligand. Significant progress has been made in the molecular dissection of the regulation of the activity of the ligands and their intracellular signal transduction pathways, including via the canonical Smad pathway where Smads interact with many transcription factors. This knowledge together with results from functional studies within the embryology and stem cell research fields is giving us insight in the role of individual ligands and other components of this signaling system and where and how it regulates many properties of embryonic and adult stem/progenitor cells, which is anticipated to contribute to successful cell-based therapy in the future.We review and discuss recent progress on the effects of Nodal/Activin and Bone Morphogenetic Proteins (BMPs) and their canonical signaling in cells with stem cell properties. We focus on embryonic stem cells and their maintenance and pluripotency, and conversion into selected cell types of neuroectoderm, mesoderm and endoderm, on induced pluripotent cells and on neurogenic cells in the adult brain.Transforming Growth Factor type β and Smad family signaling in stem cell functionEve Seuntjens, Lieve Umans, An Zwijsen, Maurilio Sampaolesi, Catherine M. Verfaillie, Danny Huylebroeck10.1016/j.cytogfr.2009.10.005Cytokine & Growth Factor Reviews 20, 5 (2009)2009-11-05Cytokine & Growth Factor Reviews2009-11-05205-6S1359-6101(09)X0006-7449458http://www.cgfr.co.uk/article/PIIS1359610109000884/abstract?rss=yesAbstract: Normal tissue development and function are regulated by the interplay between cells and their surrounding extracellular matrix (ECM). The ECM provides biochemical and mechanical contextual information that is conveyed from the cell membrane through the cytoskeleton to the nucleus to direct cell phenotype. Cells, in turn, remodel the ECM and thereby sculpt their local microenvironment. Here we review the mechanisms by which cells interact with, respond to, and influence the ECM, with particular emphasis placed on the role of this bidirectional communication during tissue morphogenesis. We also discuss the implications for successful engineering of functional tissues ex vivo.Bidirectional extracellular matrix signaling during tissue morphogenesisNikolce Gjorevski, Celeste M. Nelson10.1016/j.cytogfr.2009.10.013Cytokine & Growth Factor Reviews 20, 5 (2009)2009-11-09Cytokine & Growth Factor Reviews2009-11-09205-6S1359-6101(09)X0006-7459465http://www.cgfr.co.uk/article/PIIS1359610109000847/abstract?rss=yesAbstract: Chronic joint diseases have a major impact on society as patients suffer from pain and disability. The spectrum of arthritic disorders is wide including autoimmune and autoinflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis and related spondyloarthritides but also the more prevalent osteoarthritic diseases. The latter appear to be mainly the consequence of injury, strain and aging in a predisposing genetic background. The therapeutic options for chronic inflammatory and immune joint diseases have greatly increased over the last decade by the use of targeted anti-cytokine or anti-immune cell drugs. However, such a shift towards successful treatment has not been achieved for osteoarthritis. In addition, control of inflammation does not equal cure of the disease as relapse occurs as soon as the treatment is interrupted, and only limited tissue repair has been observed. Bone morphogenetic proteins are potent regulators of cell proliferation, differentiation and apoptosis and they have come into the spotlight in arthritis research. Here, we summarize the recent data on the role of bone morphogenetic proteins in joint protection and repair and but also their potential disease promoting or controlling roles. These data are presented in the context of a systems biology view of joint diseases based on their histomorphological phenotype rather than on existing clinical classifications.Bone morphogenetic protein signaling and arthritisRik J.U. Lories, Frank P. Luyten10.1016/j.cytogfr.2009.10.009Cytokine & Growth Factor Reviews 20, 5 (2009)2009-11-09Cytokine & Growth Factor Reviews2009-11-09205-6S1359-6101(09)X0006-7467473http://www.cgfr.co.uk/article/PIIS1359610109000938/abstract?rss=yesAbstract: BMPs are best known for their actions as bone formation signals. Recent studies using transgenic mice in which individual osteogenic BMPs have been removed from the limb skeleton have identified BMP2 as a fundamental component of the inherent regenerative capacity of bone. This review summarizes current findings on the specific requirement for BMP2 in bone formation and repair.BMP2 signaling in bone development and repairVicki Rosen10.1016/j.cytogfr.2009.10.018Cytokine & Growth Factor Reviews 20, 5 (2009)2009-11-05Cytokine & Growth Factor Reviews2009-11-05205-6S1359-6101(09)X0006-7475480http://www.cgfr.co.uk/article/PIIS1359610109000781/abstract?rss=yesAbstract: Bone healing is a predictable process that has a high rate of success. For some patients, and in certain clinical settings, this process can be delayed or completely inhibited. This leads to significant morbidity and may also result in time lost from work, costs related to prolonged medical treatment, and continued pain at the site of nonunion or failed spinal fusion. Several growth factors, specifically BMP-2 and BMP-7, have been approved in several countries for specific indications. The use of these products and potential complications of their use are reviewed.Bone morphogenetic proteins in orthopaedic surgeryT. William Axelrad, Thomas A. Einhorn10.1016/j.cytogfr.2009.10.003Cytokine & Growth Factor Reviews 20, 5 (2009)2009-11-05Cytokine & Growth Factor Reviews2009-11-05205-6S1359-6101(09)X0006-7481488http://www.cgfr.co.uk/article/PIIS1359610109000914/abstract?rss=yesAbstract: ‘Bone: Formation by autoinduction’, initiates by invocation of soluble molecular signals which, when combined to insoluble signals or substrata trigger the ripple-like cascade of bone differentiation by induction. The osteogenic proteins of the transforming growth factor-β (TGF-β) superfamily, the bone morphogenetic/osteogenic proteins (BMPs/OPs), and uniquely in the non-human primate Papio ursinus also the three mammalian TGF-β isoforms, induce endochondral bone formation as recapitulation of embryonic development. The pleiotropic activities of the BMPs/OPs are vast and include the induction of periodontal tissue regeneration. Implantation of naturally derived highly purified osteogenic fractions after sequential adsorption/affinity and gel filtration chromatography in mandibular Class II furcation defects of P. ursinus induces cementogenesis as highly cellular collagenic cementoid attached to the exposed dentine with foci of nascent mineralization with inserted de novo generated Sharpey's fibres. Recombinant human osteogenic protein-1 (hOP-1) when implanted in Class II furcation defects of P. ursinus with surgically exposed dentine matrix preferentially initiates the induction of cementogenesis; on the other hand, hBMP-2 preferentially induces alveolar bone regeneration with mineralized bone covered by prominent osteoid seams. Long-term studies with gamma-irradiated 0.5 and 2.5mg hOP-1 per gram of xenogeneic bovine collagenous matrix induce the restitutio ad integrum of the periodontal tissues in furcation defects exposed by chronic periodontitis in P. ursinus. A challenging question for tissue engineering and regenerative medicine is whether the presence of molecularly different osteogenic proteins of the TGF-β superfamily has a therapeutic significance. Mechanistically, the specificity of hOP-1 primarily initiating cementogenesis in periodontal defects is regulated by both the dentine extracellular matrix upon which responding cells attach and differentiate, and the structure/activity profile of the implanted hOP-1; the limited induction of cementogenesis by hBMP-2 in furcation defects of non-human primate and canine models is consistent with the reported data that hBMP-2 inhibits differentiation and mineralization of cementoblasts in vitro aside the specific structure/activity profile of the implanted hBMP-2 protein. The induction of periodontal tissue regeneration develops as a mosaic structure in which the osteogenic proteins of the TGF-β superfamily singly, synergistically and synchronously initiate and maintain tissue induction and morphogenesis as a recapitulation of embryonic development.Bone morphogenetic proteins, cementogenesis, myoblastic stem cells and the induction of periodontal tissue regenerationUgo Ripamonti, Jean-Claude Petit10.1016/j.cytogfr.2009.10.016Cytokine & Growth Factor Reviews 20, 5 (2009)2009-11-09Cytokine & Growth Factor Reviews2009-11-09205-6S1359-6101(09)X0006-7489499http://www.cgfr.co.uk/article/PIIS1359610109000768/abstract?rss=yesAbstract: Bone morphogenetic proteins (BMPs) are growth factors belonging to the TGF beta super family. To date, more than twenty human BMPs have been identified. Of these, BMP-2 and BMP-7 (also known as osteogenic protein 1 or OP-1) are the only BMPs used clinically. Recombinant forms of both proteins are currently being implanted surgically to induce spinal fusion and to treat long bone non-union fractures. However, in both indications, large quantities of recombinant proteins are needed to induce new bone formation. This translates to higher costs and potential safety risks. Various genetic engineering approaches are being considered to produce second generation BMPs with improved safety and efficacy profiles. Modified BMPs with one or more of the following characteristics are being considered: (i) improved binding affinity to specific target cell surface BMP receptors, (ii) decreased sensitivity to natural BMP inhibitors, (iii) better immunogenicity profile, and (iv) increased solubility and stability, to cite a few. This review summarizes the progress made so far in this field and gives a perspective on what the next generation BMPs could look like.Design of second generation therapeutic recombinant bone morphogenetic proteinsMoulay Hicham Alaoui-Ismaili, Dean Falb10.1016/j.cytogfr.2009.10.001Cytokine & Growth Factor Reviews 20, 5 (2009)2009-11-12Cytokine & Growth Factor Reviews2009-11-12205-6S1359-6101(09)X0006-7501507http://www.cgfr.co.uk/article/PIIS1359610109000860/abstract?rss=yesAbstract: Much evidence suggests that “developmental regulator” genes, like those encoding transcription factors and signaling molecules, are typically controlled by many modular, tissue-specific cis-regulatory elements that function during embryogenesis. These elements are often far from gene coding regions and promoters. Bone morphogenetic proteins (BMPs) drive many processes in development relating to organogenesis and differentiation. Four BMP family members, Bmp2, Bmp4, Bmp5, and Gdf6, are now known to be under the control of distant cis-regulatory elements. BMPs are thus firmly placed in the category of genes prone to this phenomenon. The analysis of distant BMP regulatory elements has provided insight into the many pleiotropic effects of BMP genes, and underscores the biological importance of non-coding genomic DNA elements.Control of BMP gene expression by long-range regulatory elementsSteven Pregizer, Douglas P. Mortlock10.1016/j.cytogfr.2009.10.011Cytokine & Growth Factor Reviews 20, 5 (2009)2009-11-09Cytokine & Growth Factor Reviews2009-11-09205-6S1359-6101(09)X0006-7509515http://www.cgfr.co.uk/article/PIIS1359610109000793/abstract?rss=yesAbstract: microRNAs (miRNAs) are small, non-coding RNAs that modulate diverse biological functions through the repression of target genes. miRNA profiling studies have indicated that the levels of miRNAs are altered during normal development and pathogenesis of various diseases, including cancer and cardiovascular disorders. The signaling pathways which control miRNA biogenesis and the mechanisms of regulation, however, are not well understood. Following transcription, mature miRNAs are generated through a series of coordinated processing events mediated by large protein complexes. We recently found that signal transducers of the Transforming Growth Factor β (TGFβ) signaling pathway, the Smads, play a regulatory role in the processing of miRNA in the nucleus. In this review, we summarize the current understanding of the regulation of miRNA biogenesis mediated by the TGFβ signaling pathway.Control of microRNA biogenesis by TGFβ signaling pathway—A novel role of Smads in the nucleusAkiko Hata, Brandi N. Davis10.1016/j.cytogfr.2009.10.004Cytokine & Growth Factor Reviews 20, 5 (2009)2009-11-05Cytokine & Growth Factor Reviews2009-11-05205-6S1359-6101(09)X0006-7517521http://www.cgfr.co.uk/article/PIIS135961010900094X/abstract?rss=yesAbstract: Bone morphogenetic proteins (BMPs) regulate many processes in embryonic development as well as in the maintenance of normal tissue function later in adult life. However, the role of this family of proteins in formation of adipose tissue has been underappreciated in the field of developmental biology. With the growing epidemic of obesity, improved knowledge of adipocyte development and function is urgently needed. Recently, there have been significant advances in understanding the role of different members of the BMP superfamily in control of adipocyte differentiation and systemic energy homeostasis. This review summarizes recent progress in understanding how BMPs specify adipose cell fate in stem/progenitor cells and their potential role in energy metabolism. We propose that BMPs provide instructive signals for adipose cell fate determination and regulate adipocyte function. These findings have opened up exciting opportunities for developing new therapeutic approaches for the treatment of obesity and its many associated metabolic disorders.Emerging role of bone morphogenetic proteins in adipogenesis and energy metabolismTim J. Schulz, Yu-Hua Tseng10.1016/j.cytogfr.2009.10.019Cytokine & Growth Factor Reviews 20, 5 (2009)2009-11-09Cytokine & Growth Factor Reviews2009-11-09205-6S1359-6101(09)X0006-7523531