TGFβ2 mediates the effects of Hedgehog on hypertrophic differentiation and PTHrP expression

Development ◽  
2002 ◽  
Vol 129 (8) ◽  
pp. 1913-1924 ◽  
Author(s):  
Jesus Alvarez ◽  
Philip Sohn ◽  
Xin Zeng ◽  
Thomas Doetschman ◽  
David J. Robbins ◽  
...  
Keyword(s):  
Growth Plate ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Signaling Cascade ◽  
Tgfβ Signaling ◽  
Organ Cultures ◽  
Embryonic Mouse ◽  
Metatarsal Bones ◽  
Pthrp Expression

The development of endochondral bones requires the coordination of signals from several cell types within the cartilage rudiment. A signaling cascade involving Indian hedgehog (Ihh) and parathyroid hormone related peptide (PTHrP) has been described in which hypertrophic differentiation is limited by a signal secreted from chondrocytes as they become committed to hypertrophy. In this negative-feedback loop, Ihh inhibits hypertrophic differentiation by regulating the expression of Pthrp, which in turn acts directly on chondrocytes in the growth plate that express the PTH/PTHrP receptor. Previously, we have shown that PTHrP also acts downstream of transforming growth factor β (TGFβ) in a common signaling cascade to regulate hypertrophic differentiation in embryonic mouse metatarsal organ cultures. As members of the TGFβ superfamily have been shown to mediate the effects of Hedgehog in several developmental systems, we proposed a model where TGFβ acts downstream of Ihh and upstream of PTHrP in a cascade of signals that regulate hypertrophic differentiation in the growth plate. This report tests the hypothesis that TGFβ signaling is required for the effects of Hedgehog on hypertrophic differentiation and expression of Pthrp. We show that Sonic hedgehog (Shh), a functional substitute for Ihh, stimulates expression of Tgfb2 and Tgfb3 mRNA in the perichondrium of embryonic mouse metatarsal bones grown in organ cultures and that TGFβ signaling in the perichondrium is required for inhibition of differentiation and regulation of Pthrp expression by Shh. The effects of Shh are specifically dependent on TGFβ2, as cultures from Tgfb3-null embryos respond to Shh but cultures from Tgfb2-null embryos do not. Taken together, these data suggest that TGFβ2 acts as a signal relay between Ihh and PTHrP in the regulation of cartilage hypertrophic differentiation.

scholarly journals TGFβ family signaling and development

Development ◽  
2021 ◽  
Vol 148 (5) ◽  
Author(s):  
Shunji Jia ◽  
Anming Meng
Keyword(s):  
Signal Transduction ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Family Members ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Dorsoventral Patterning ◽  
Tgfβ Signaling ◽  
Evolutionarily Conserved ◽  
Transduction Mechanisms

ABSTRACT The transforming growth factor β (TGFβ) signaling family is evolutionarily conserved in metazoans. The signal transduction mechanisms of TGFβ family members have been expansively investigated and are well understood. During development and homeostasis, numerous TGFβ family members are expressed in various cell types with temporally changing levels, playing diverse roles in embryonic development, adult tissue homeostasis and human diseases by regulating cell proliferation, differentiation, adhesion, migration and apoptosis. Here, we discuss the molecular mechanisms underlying signal transduction and regulation of the TGFβ subfamily pathways, and then highlight their key functions in mesendoderm induction, dorsoventral patterning and laterality development, as well as in the formation of several representative tissues/organs.

scholarly journals Actin Cytoskeleton and Regulation of TGFβ Signaling: Exploring Their Links

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 336
Author(s):  
Roberta Melchionna ◽  
Paola Trono ◽  
Annalisa Tocci ◽  
Paola Nisticò
Keyword(s):  
Cancer Progression ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Tissue Homeostasis ◽  
Actin Dynamics ◽  
Human Tissues ◽  
Cellular Functions ◽  
Tgfβ Signaling ◽  
Physical Mechanisms ◽  
And Function

Human tissues, to maintain their architecture and function, respond to injuries by activating intricate biochemical and physical mechanisms that regulates intercellular communication crucial in maintaining tissue homeostasis. Coordination of the communication occurs through the activity of different actin cytoskeletal regulators, physically connected to extracellular matrix through integrins, generating a platform of biochemical and biomechanical signaling that is deregulated in cancer. Among the major pathways, a controller of cellular functions is the cytokine transforming growth factor β (TGFβ), which remains a complex and central signaling network still to be interpreted and explained in cancer progression. Here, we discuss the link between actin dynamics and TGFβ signaling with the aim of exploring their aberrant interaction in cancer.

scholarly journals Skeletal Deformities in Osterix-Cre;Tgfbr2f/f Mice May Cause Postnatal Death

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 975
Author(s):  
Kara Corps ◽  
Monica Stanwick ◽  
Juliann Rectenwald ◽  
Andrew Kruggel ◽  
Sarah B. Peters
Keyword(s):  
Transforming Growth Factor ◽  
Skeletal Development ◽  
Transforming Growth Factor Β ◽  
Tgfβ Signaling ◽  
Skeletal Deformities ◽  
Tooth Abnormalities ◽  
Pathological Analysis ◽  
Diaphragmatic Muscle ◽  
Proliferation And Differentiation ◽  
Tgfβ Receptor

Transforming growth factor β (TGFβ) signaling plays an important role in skeletal development. We previously demonstrated that the loss of TGFβ receptor II (Tgfbr2) in Osterix-Cre-expressing mesenchyme results in defects in bones and teeth due to reduced proliferation and differentiation in pre-osteoblasts and pre-odontoblasts. These Osterix-Cre;Tgfbr2f/f mice typically die within approximately four weeks for unknown reasons. To investigate the cause of death, we performed extensive pathological analysis on Osterix-Cre- (Cre-), Osterix-Cre+;Tgfbr2f/wt (HET), and Osterix-Cre+;Tgfbr2f/f (CKO) mice. We also crossed Osterix-Cre mice with the ROSA26mTmG reporter line to identify potential off-target Cre expression. The findings recapitulated published skeletal and tooth abnormalities and revealed previously unreported osteochondral dysplasia throughout both the appendicular and axial skeletons in the CKO mice, including the calvaria. Alterations to the nasal area and teeth suggest a potentially reduced capacity to sense and process food, while off-target Cre expression in the gastrointestinal tract may indicate an inability to absorb nutrients. Additionally, altered nasal passages and unexplained changes in diaphragmatic muscle support the possibility of hypoxia. We conclude that these mice likely died due to a combination of breathing difficulties, malnutrition, and starvation resulting primarily from skeletal deformities that decreased their ability to sense, gather, and process food.

scholarly journals A pulsatile release platform based on photo-induced imine-crosslinking hydrogel promotes scarless wound healing

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jian Zhang ◽  
Yongjun Zheng ◽  
Jimmy Lee ◽  
Jieyu Hua ◽  
Shilong Li ◽  
...  
Keyword(s):  
Wound Healing ◽  
Wound Repair ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Skin Wound ◽  
Large Animal ◽  
Skin Wounds ◽  
Tgfβ Signaling ◽  
Pulsatile Release ◽  
Ecm Extracellular Matrix

AbstractEffective healing of skin wounds is essential for our survival. Although skin has strong regenerative potential, dysfunctional and disfiguring scars can result from aberrant wound repair. Skin scarring involves excessive deposition and misalignment of ECM (extracellular matrix), increased cellularity, and chronic inflammation. Transforming growth factor-β (TGFβ) signaling exerts pleiotropic effects on wound healing by regulating cell proliferation, migration, ECM production, and the immune response. Although blocking TGFβ signaling can reduce tissue fibrosis and scarring, systemic inhibition of TGFβ can lead to significant side effects and inhibit wound re-epithelization. In this study, we develop a wound dressing material based on an integrated photo-crosslinking strategy and a microcapsule platform with pulsatile release of TGF-β inhibitor to achieve spatiotemporal specificity for skin wounds. The material enhances skin wound closure while effectively suppressing scar formation in murine skin wounds and large animal preclinical models. Our study presents a strategy for scarless wound repair.

scholarly journals Fibroblasts Influence the Efficacy, Resistance, and Future Use of Vaccines and Immunotherapy in Cancer Treatment

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 634
Author(s):  
Bailee H. Sliker ◽  
Paul M. Campbell
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Fibroblast Activation Protein ◽  
Cancer Associated Fibroblasts ◽  
Cell Type ◽  
Adaptive Immune ◽  
Adaptive Immune Cells ◽  
New Research ◽  
Tumor Types

Tumors are composed of not only epithelial cells but also many other cell types that contribute to the tumor microenvironment (TME). Within this space, cancer-associated fibroblasts (CAFs) are a prominent cell type, and these cells are connected to an increase in tumor progression as well as alteration of the immune landscape present in and around the tumor. This is accomplished in part by their ability to alter the presence of both innate and adaptive immune cells as well as the release of various chemokines and cytokines, together leading to a more immunosuppressive TME. Furthermore, new research implicates CAFs as players in immunotherapy response in many different tumor types, typically by blunting their efficacy. Fibroblast activation protein (FAP) and transforming growth factor β (TGF-β), two major CAF proteins, are associated with the outcome of different immunotherapies and, additionally, have become new targets themselves for immune-based strategies directed at CAFs. This review will focus on CAFs and how they alter the immune landscape within tumors, how this affects response to current immunotherapy treatments, and how immune-based treatments are currently being harnessed to target the CAF population itself.

scholarly journals The noncoding MIR100HG RNA enhances the autocrine function of transforming growth factor β signaling

Oncogene ◽  
2021 ◽  
Author(s):  
Panagiotis Papoutsoglou ◽  
Dorival Mendes Rodrigues-Junior ◽  
Anita Morén ◽  
Andrew Bergman ◽  
Fredrik Pontén ◽  
...  
Keyword(s):  
Growth Factor ◽  
Target Genes ◽  
Rna Binding ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Tgfβ Signaling ◽  
Ribonucleoprotein Complexes ◽  
Expression Of Genes ◽  
Downstream Effectors ◽  
Human Carcinomas

AbstractActivation of the transforming growth factor β (TGFβ) pathway modulates the expression of genes involved in cell growth arrest, motility, and embryogenesis. An expression screen for long noncoding RNAs indicated that TGFβ induced mir-100-let-7a-2-mir-125b-1 cluster host gene (MIR100HG) expression in diverse cancer types, thus confirming an earlier demonstration of TGFβ-mediated transcriptional induction of MIR100HG in pancreatic adenocarcinoma. MIR100HG depletion attenuated TGFβ signaling, expression of TGFβ-target genes, and TGFβ-mediated cell cycle arrest. Moreover, MIR100HG silencing inhibited both normal and cancer cell motility and enhanced the cytotoxicity of cytostatic drugs. MIR100HG overexpression had an inverse impact on TGFβ signaling responses. Screening for downstream effectors of MIR100HG identified the ligand TGFβ1. MIR100HG and TGFB1 mRNA formed ribonucleoprotein complexes with the RNA-binding protein HuR, promoting TGFβ1 cytokine secretion. In addition, TGFβ regulated let-7a-2–3p, miR-125b-5p, and miR-125b-1–3p expression, all encoded by MIR100HG intron-3. Certain intron-3 miRNAs may be involved in TGFβ/SMAD-mediated responses (let-7a-2–3p) and others (miR-100, miR-125b) in resistance to cytotoxic drugs mediated by MIR100HG. In support of a model whereby TGFβ induces MIR100HG, which then enhances TGFβ1 secretion, analysis of human carcinomas showed that MIR100HG expression correlated with expression of TGFB1 and its downstream extracellular target TGFBI. Thus, MIR100HG controls the magnitude of TGFβ signaling via TGFβ1 autoinduction and secretion in carcinomas.

scholarly journals Abrogation of Transforming Growth Factor-β Type II Receptor Stimulates Embryonic Mouse Lung Branching Morphogenesis in Culture

1996 ◽  
Vol 180 (1) ◽  
pp. 242-257 ◽  
Author(s):  
Jingsong Zhao ◽  
Ding Bu ◽  
Matt Lee ◽  
Harold C. Slavkin ◽  
Frederick L. Hall ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Branching Morphogenesis ◽  
Mouse Lung ◽  
Type Ii ◽  
Embryonic Mouse ◽  
Lung Branching

TGFβ: Signaling Blockade for Cancer Immunotherapy

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Szu-Ying Chen ◽  
Ons Mamäi ◽  
Rosemary J. Akhurst
Keyword(s):  
Cancer Biology ◽  
Transforming Growth Factor ◽  
Biological Activities ◽  
Tumor Stroma ◽  
Transforming Growth Factor Β ◽  
Therapeutic Window ◽  
Annual Review ◽  
Publication Date ◽  
Tgfβ Signaling ◽  
Mesenchymal Transformation

Discovered over four decades ago, transforming growth factor β (TGFβ) is a potent pleiotropic cytokine that has context-dependent effects on most cell types. It acts as a tumor suppressor in some cancers and/or supports tumor progression and metastasis through its effects on the tumor stroma and immune microenvironment. In TGFβ-responsive tumors it can promote invasion and metastasis through epithelial-mesenchymal transformation, the appearance of cancer stem cell features, and resistance to many drug classes, including checkpoint blockade immunotherapies. Here we consider the biological activities of TGFβ action on different cells of relevance toward improving immunotherapy outcomes for patients, with a focus on the adaptive immune system. We discuss recent advances in the development of drugs that target the TGFβ signaling pathway in a tumor-specific or cell type–specific manner to improve the therapeutic window between response rates and adverse effects. Expected final online publication date for the Annual Review of Cancer Biology, Volume 6 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Myostatin/Activin-A Signaling in the Vessel Wall and Vascular Calcification

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2070
Author(s):  
Pasquale Esposito ◽  
Daniela Verzola ◽  
Daniela Picciotto ◽  
Leda Cipriani ◽  
Francesca Viazzi ◽  
...  
Keyword(s):  
Vascular Calcification ◽  
Intracellular Signaling ◽  
Transforming Growth Factor ◽  
Vascular Inflammation ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Activin A ◽  
Premature Aging ◽  
High Morbidity ◽  
Type I

A current hypothesis is that transforming growth factor-β signaling ligands, such as activin-A and myostatin, play a role in vascular damage in atherosclerosis and chronic kidney disease (CKD). Myostatin and activin-A bind with different affinity the activin receptors (type I or II), activating distinct intracellular signaling pathways and finally leading to modulation of gene expression. Myostatin and activin-A are expressed by different cell types and tissues, including muscle, kidney, reproductive system, immune cells, heart, and vessels, where they exert pleiotropic effects. In arterial vessels, experimental evidence indicates that myostatin may mostly promote vascular inflammation and premature aging, while activin-A is involved in the pathogenesis of vascular calcification and CKD-related mineral bone disorders. In this review, we discuss novel insights into the biology and physiology of the role played by myostatin and activin in the vascular wall, focusing on the experimental and clinical data, which suggest the involvement of these molecules in vascular remodeling and calcification processes. Moreover, we describe the strategies that have been used to modulate the activin downward signal. Understanding the role of myostatin/activin signaling in vascular disease and bone metabolism may provide novel therapeutic opportunities to improve the treatment of conditions still associated with high morbidity and mortality.

Sign in / Sign up

Export Citation Format

Share Document