Bone morphogenetic proteins (BMPs) are a group of growth factors with the clinical potential to regulate cartilage and bone formation. Functionally active mature recombinant human BMPs (rhBMPs), ...produced primarily in Chinese hamster ovary (CHO) cells for clinical applications, are considered difficult to express because they undergo maturation processes, signaling pathways, or endocytosis. Although BMPs are a family of proteins with similar mature domain sequence identities, their individual properties are diverse. Thus, understanding the properties of individual rhBMPs is essential to improve rhBMP production in CHO cells. In this review, we discuss various approaches to improve rhBMP production in CHO cells by understanding the overall maturation process, signaling pathways and endocytosis of individual rhBMPs.
•BMPs are a group of growth factors with the clinical potential.•BMPs, produced primarily in CHO cells, are considered difficult to express.•BMPs undergo maturation processes, signaling pathways, or endocytosis.•BMPs have very different characteristics.•Strategies to improve the production of individual BMPs in CHO cells are discussed.
Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β (TGF-β) family that signal via type I and type II serine/threonine kinase receptors and intracellular Smad ...transcription factors. BMPs are multifunctional regulators of development and tissue homeostasis and they were initially characterized as inducers of bone regeneration. Genetic studies in humans and mice showed that perturbations in BMP signaling lead to various diseases, such as skeletal diseases, vascular diseases and cancer. Mutations in BMP type II receptor and BMP type I receptor/activin receptor-like kinase 1 have been linked to pulmonary arterial hypertension and hereditary hemorrhagic telangiectasia, respectively. BMPs have also been implicated in promoting vascular calcification and tumor angiogenesis. In this review we discuss the role of BMP signaling in vascular diseases and the value of BMP signaling as a vascular disease marker or a therapeutic target.
The TGF-β Family in Glioblastoma Golan, Irene; Caja, Laia
International journal of molecular sciences,
2024, Volume:
25, Issue:
2
Journal Article
Peer reviewed
Open access
Members of the transforming growth factor beta (TGF-beta) family have been implicated in the biology of several cancers. In this review, we focus on the role of TGF beta and bone morphogenetic ...protein (BMP) signaling in glioblastoma. Glioblastoma (GBM) is the most common malignant brain tumor in adults; it presents at a median age of 64 years, but can occur at any age, including childhood. Unfortunately, there is no cure, and even patients undergoing current treatments (surgical resection, radiotherapy, and chemotherapy) have a median survival of 15 months. There is a great need to identify new therapeutic targets to improve the treatment of GBM patients. TGF-beta s signaling promotes tumorigenesis in glioblastoma, while BMPs suppress tumorigenic potential by inducing tumor cell differentiation. In this review, we discuss the actions of TGF-beta s and BMPs on cancer cells as well as in the tumor microenvironment, and their use in potential therapeutic intervention.
Best management practices (BMPs) have been widely used to address hydrology and water quality issues in both agricultural and urban areas. Increasing numbers of BMPs have been studied in research ...projects and implemented in watershed management projects, but a gap remains in quantifying their effectiveness through time. In this paper, we review the current knowledge about BMP efficiencies, which indicates that most empirical studies have focused on short-term efficiencies, while few have explored long-term efficiencies. Most simulation efforts that consider BMPs assume constant performance irrespective of ages of the practices, generally based on anticipated maintenance activities or the expected performance over the life of the BMP(s). However, efficiencies of BMPs likely change over time irrespective of maintenance due to factors such as degradation of structures and accumulation of pollutants. Generally, the impacts of BMPs implemented in water quality protection programs at watershed levels have not been as rapid or large as expected, possibly due to overly high expectations for practice long-term efficiency, with BMPs even being sources of pollutants under some conditions and during some time periods. The review of available datasets reveals that current data are limited regarding both short-term and long-term BMP efficiency. Based on this review, this paper provides suggestions regarding needs and opportunities. Existing practice efficiency data need to be compiled. New data on BMP efficiencies that consider important factors, such as maintenance activities, also need to be collected. Then, the existing and new data need to be analyzed. Further research is needed to create a framework, as well as modeling approaches built on the framework, to simulate changes in BMP efficiencies with time. The research community needs to work together in addressing these needs and opportunities, which will assist decision makers in formulating better decisions regarding BMP implementation in watershed management projects.
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•Few studies have documented long-term BMP efficiencies on water quantity and quality.•Most simulation efforts have assumed constant long-term BMP performance.•Efficiencies of BMPs likely change over time irrespective of maintenance.•Limited empirical data have been collected to describe the performance of BMPs.•Needs and opportunities for quantifying effectiveness of BMPs are provided.
Regenerative medicine has sparked interest in potential strategies for bone repair. Bone defects are widespread and could be caused by trauma, congenital malformations, infections, and surgery. ...Although bone has a large self‐healing capacity, some defects or fractures are too big to regenerate. To regenerate bone structures which can be used for treatment of patients, bone growth must be induced by a number of bioactive implantable materials, cell types and intracellular, and extracellular molecular signaling pathways. Since mesenchymal stem cells (MSCs) and their differentiation during remodeling processes have important roles in bone regeneration, it is believed that understanding molecular signaling pathways involved is crucial to the development of bone implants, bone substitute materials, and cell‐based scaffolds for bone regeneration. In this review, we briefly introduce concepts in fracture repair and regeneration following bone injuries, and then discuss the current clinical methods in bone regeneration. In the next section, we review the involvement of the various key signaling pathways in bone regeneration.
•The national BMP implementation rate was 91% (32 states reported data).•State BMP regulation did not have an effect on mean state implementation rates.•Mean state BMP implementation rates were lower ...for the northeastern region.•Thirty-three states reported having conducted BMP effectiveness studies.•Twenty-five states written or revised BMP guidelines within five years of the survey.
United States forestry best management practices (BMPs) were developed by U.S. states to protect water quality while enhancing the sustainability of forest management activities. Forestry BMPs are revised over time or new BMPs are written to meet current water quality standards. Properly implemented forestry BMPs have been found to minimize the impact of erosion and sediment that may occur during forest management activities. States developed implementation strategies to help determine if BMPs are being implemented correctly; however, these strategies can vary between regions and states making implementation results difficult to interpret. Few studies have compared monitoring strategies and implementation of BMPs on a national level. This study surveyed and received responses from state forestry agencies in all 50 states. Each state reported a documented BMP manual. Twenty states reported non-regulatory BMP guidelines, 19 reported quasi-regulatory BMP guidelines, and 11 reported regulatory BMP guidelines. Thirty-nine states have BMP monitoring programs with the state forestry agency as the lead agency in 35 states. BMP effectiveness studies were reported in 33 states with 19 states reporting current or future effectiveness studies. Thirty-two states reported that they have conducted BMP implementation studies resulting in a mean national BMP implementation rate of 91%. However, when evaluating implementation of individual BMP categories, the survey indicated potential deficiencies for some states, yet these states’ overall BMP implementation rate appear to be satisfactory. There was no significant difference between non-regulatory, quasi-regulatory, and regulatory BMP guidelines when compared by mean state BMP implementation rates (90.2%, 90.2%, and 93.4%, respectively). Mean BMP implementation rates for the western (93.2%) and southeastern (92.4%) regions were significantly higher than the northeastern region (86.4%). This assessment of state BMP programs indicates that BMP programs appear to be implemented at relatively high levels across the U.S. These findings should be useful globally for agency managers to improve program effectiveness and better understand BMP implementation and program structure among 50 diverse states.
•Literature review of forestry best management practice (BMP) effectiveness studies.•Reviewed thirty research studies in the southern United States.•Reviewed twenty research studies in the northern ...United States.•Reviewed thirty-one research studies in the western United States.•Literature indicates that water quality is protected when BMPs are properly applied.
In response to the Federal Water Pollution Control Act (a.k.a., Clean Water Act) of 1972, forestry best management practices (BMPs) were developed and subsequently implemented to address NPS pollution during forest management. BMP guidelines vary by state and can be non-regulatory, quasi-regulatory, or regulatory. To determine how effective the guidelines for protecting water quality are, research literature relating to BMP effectiveness was evaluated. Forestry BMP effectiveness studies are often site or region specific. Therefore, BMP research in the United States was divided into three regions: northern, southern, and western. Thirty research studies were reviewed for the southern region with the majority being conducted in the Piedmont and Coastal Plain physiographic regions. The western region had thirty-one studies, most of which were in the Pacific Border physiographic region. The northern region had twenty studies primarily in the northeastern states. Forestry BMP effectiveness research generally focused on forest water quality from timber harvesting, site preparation, forest road construction and maintenance, stream crossings, and other categories of forest operations. The literature indicates that forestry BMPs protect water quality when constructed correctly and in adequate numbers. Forestry BMP effectiveness studies allow state forestry BMP programs to evaluate progress in reducing non-point source pollution and achieving water quality goals established under the Clean Water Act (CWA). Furthermore, states have used research findings to change BMPs and improve their guidelines. Although forestry BMPs have been proven to protect water quality, they are still being refined to enhance their performance.
BMPs were purified from demineralized bone matrix based on their ability to induce new bone in vivo and they represent a large member of the TGF-β superfamily of proteins. BMPs serve as morphogenic ...signals for mesenchymal stem cell migration, proliferation and subsequently differentiation into cartilage and bone during embryonic development. A BMP when implanted with a collagenous carrier in a rat subcutaneous site is capable of inducing new bone by mimicking the cellular events of embryonic bone formation. Based on this biological principle, BMP2 and BMP7 containing collagenous matrix as carrier have been developed as bone graft substitutes for spine fusion and long bone fractures. Here, we describe a novel autologous bone graft substitute that contains BMP6 delivered within an autologous blood coagulum as carrier and summarize the biology of osteogenic BMPs in the context of bone repair and regeneration specifically the critical role that carrier plays to support osteogenesis.
•Biology of BMP in Bone Repair•BMP2, BMP6, BMP7•Autologous Blood Coagulum as Carrier for BMP
Summary
Osteoblasts and adipocytes originate from a common progenitor, which arises from bone marrow mesenchymal stroma/stem cells (mMSC). Aging causes a decrease in the number of bone‐forming ...osteoblasts and an increase in the number of marrow adipocytes. Here, we demonstrate that, during aging, the status of mMSC changes with respect to both their intrinsic differentiation potential and production of signaling molecules, which contributes to the formation of a specific marrow microenvironment necessary for maintenance of bone homeostasis. Aging causes a decrease in the commitment of mMSC to the osteoblast lineage and an increase in the commitment to the adipocyte lineage. This is reflected by changes in the expression of phenotype‐specific gene markers. The expression of osteoblast‐specific transcription factors, Runx2 and Dlx5, and osteoblast markers, collagen and osteocalcin, is decreased in aged mMSC. Conversely, the expression of adipocyte‐specific transcription factor PPAR‐γ2, shown previously to regulate osteoblast development and bone formation negatively and to regulate marrow adipocyte differentiation positively, is increased, as is a gene marker of adipocyte phenotype, fatty acid binding protein aP2. Furthermore, production of an endogeneous PPAR‐γ activator(s) that stimulates adipocyte differentiation and production of autocrine/paracrine factor(s) that suppresses the osteoblastic phenotype are also increased. In addition, expression of different components of TGF‐β and BMP2/4 signaling pathways is altered, suggesting that activities of these two cytokines essential for bone homeostasis change with aging.
Cerebral cavernous malformations (CCMs) are vascular malformations located within the central nervous system often resulting in cerebral hemorrhage. Pharmacological treatment is needed, since current ...therapy is limited to neurosurgery. Familial CCM is caused by loss‐of‐function mutations in any of Ccm1, Ccm2, and Ccm3 genes. CCM cavernomas are lined by endothelial cells (ECs) undergoing endothelial‐to‐mesenchymal transition (EndMT). This switch in phenotype is due to the activation of the transforming growth factor beta/bone morphogenetic protein (TGFβ/BMP) signaling. However, the mechanism linking Ccm gene inactivation and TGFβ/BMP‐dependent EndMT remains undefined. Here, we report that Ccm1 ablation leads to the activation of a MEKK3‐MEK5‐ERK5‐MEF2 signaling axis that induces a strong increase in Kruppel‐like factor 4 (KLF4) in ECs in vivo. KLF4 transcriptional activity is responsible for the EndMT occurring in CCM1‐null ECs. KLF4 promotes TGFβ/BMP signaling through the production of BMP6. Importantly, in endothelial‐specific Ccm1 and Klf4 double knockout mice, we observe a strong reduction in the development of CCM and mouse mortality. Our data unveil KLF4 as a therapeutic target for CCM.
Synopsis
Current therapy for cerebral cavernous malformation (CCM) therapy is limited to neurosurgery. Transcription factor KLF4 is found to be a crucial determinant for the development of cavernomas and thus a future therapeutic target.
KLF4 is strongly upregulated in endothelial cells in the absence of any of the three CCM genes.
The endothelial‐to‐mesenchymal transition observed in endothelial cells null for CCM1 is induced by KLF4.
KLF4 activates TGFβ/BMP signaling by increasing Bmp6 expression in endothelial cells in the absence of CCM1.
The development and progression of cavernomas is strongly reduced upon genetic Klf4 inactivation.
KLF4 is a strong candidate as a novel target for the pharmacological treatment of CCM, since its inactivation reduces mouse mortality associated to this disease by 75%.
Current therapy for cerebral cavernous malformation (CCM) therapy is limited to neurosurgery. Transcription factor KLF4 is found to be a crucial determinant for the development of cavernomas and thus a future therapeutic target.
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