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Proteomic and genomic analysis of acid dentin lysate with focus on TGF-β signaling.

ABSTRACT: Particulate autologous tooth roots are increasingly used for alveolar bone augmentation; however, the proteomic profile of acid dentin lysate and the respective cellular response have not been investigated. Here we show that TGF-β1 is among the 226 proteins of acid dentin lysate (ADL) prepared from porcine teeth. RNA sequencing identified 231 strongly regulated genes when gingival fibroblasts were exposed to ADL. Out of these genes, about one third required activation of the TGF-β receptor type I kinase including interleukin 11 (IL11) and NADPH oxidase 4 (NOX4). Reverse transcription-quantitative polymerase chain reaction and immunoassay confirmed the TGF-β-dependent expression of IL11 and NOX4. The activation of canonical TGF-β signaling by ADL was further confirmed by the phosphorylation of Smad3 and translocation of Smad2/3, using Western blot and immunofluorescence staining, respectively. Finally, we showed that TGF-β activity released from dentin by acid lysis adsorbs to titanium and collagen membranes. These findings suggest that dentin particles are a rich source of TGF-β causing a major response of gingival fibroblasts.

SUBMITTER: Nasirzade J

PROVIDER: S-EPMC8192760 | biostudies-literature |

REPOSITORIES: biostudies-literature

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TGF-β activity in acid bone lysate adsorbs to titanium surface.

Project description:ObjectivesOsteoblasts lay down new bone on implant surfaces. The underlying cellular mechanism and the spatio-temporal mode of action, however, remain unclear. It can be proposed that growth factors released upon acidification by osteoclasts adsorb to the implant surface and control the early stages of osseointegration.MethodsTo simulate bone lysis by osteoclasts, titanium discs were exposed to acid bone lysate (ABL) followed by vigorous washing and seeding of oral fibroblasts. The expression of TGF-β target genes interleukin 11 (IL11) and NADPH oxidase 4 (NOX4) was evaluated by reverse transcriptase polymerase chain reaction and IL11 ELISA. TGF-β signaling activation was assessed via Smad2/3 immunofluorescence. The impact of ABL on osteogenic differentiation was determined with murine ST2 mesenchymal stromal cells.ResultsWe report here that ABL-conditioned titanium discs, independent of turned or rough surface, increased the expression of IL11 and NOX4. This increase was blocked by the TGF-β receptor 1 antagonist SB431542. Further support for the TGF-β signaling activation came from the translocation of Smad2/3 into the nucleus of oral fibroblasts. Moreover, titanium discs exposed to ABL decreased alkaline phosphatase and osteopontin in ST2 cells.ConclusionsThese in vitro findings suggest that titanium can adsorb TGF-β from ABLs. The data provide a strong impetus for studies on the protein adsorption on implant surfaces in vitro and in vivo, specifically for growth factors including bone-derived TGF-β during successful and failed osseointegration.

| S-EPMC6593995 | biostudies-literature

Acid Dentin Lysate Modulates Macrophage Polarization and Osteoclastogenesis In Vitro.

Project description:Dentin prepared from extracted teeth is used as autograft for alveolar bone augmentation. Graft consolidation involves the acid lysis of dentin thereby generating a characteristic paracrine environment. Acid lysate of dentin is mimicking this environment. Acid dentin lysate (ADL) potentially targets hematopoietic cells thereby affecting their differentiation towards macrophages and osteoclasts; however, the question remains if ADL controls macrophage polarization and osteoclastogenesis. Here, we show that ADL reduced lipopolysaccharide (LPS)-induced macrophage polarization of the pro-inflammatory (M1) phenotype, indicated by attenuated Interleukin 1 (IL1), Interleukine 6 (IL6)and cyclooxygenase 2 (COX2) expression. This decrease in M1 macrophages was confirmed by the reduced phosphorylation and nuclear translocation of p65 in the LPS-exposed RAW 264.7 macrophages. Similarly, when RAW 264.7 macrophages were incubated with other agonists of Toll-like receptor (TLR) signaling e.g., FSL1, Polyinosinic-polycytidylic acid High Molecular Weight (Poly (1:C) HMW), Pam3CSK4, and imiquimod, ADL reduced the IL6 expression. We further show herein that ADL decreased osteoclastogenesis indicated by the reduced formation of multinucleated cell expressing cathepsin K and tartrate-resistant acid phosphatase in murine bone marrow cultures. Overall, our results suggest that acid dentin lysate can affect the differentiation of hematopoietic cells to M1 macrophage polarization and a decrease in osteoclastogenesis in bone marrow cultures.

| S-EPMC8622705 | biostudies-literature

Fatty acid synthase is required for profibrotic TGF-β signaling.

Project description:Evidence is provided that the fibroproliferative actions of TGF-β are dependent on a metabolic adaptation that sustains pathologic growth. Specifically, profibrotic TGF-β signaling is shown to require fatty acid synthase (FASN), an essential anabolic enzyme responsible for the de novo synthesis of fatty acids. With the use of pharmacologic and genetic approaches, we show that TGF-β-stimulated FASN expression is independent of Smad2/3 and is mediated via mammalian target of rapamycin complex 1. In the absence of FASN activity or protein, TGF-β-driven fibrogenic processes are reduced with no apparent toxicity. Furthermore, as increased FASN expression was also observed to correlate with the degree of lung fibrosis in bleomycin-treated mice, inhibition of FASN was examined in a murine-treatment model of pulmonary fibrosis. Remarkably, inhibition of FASN not only decreased expression of profibrotic targets, but lung function was also stabilized/improved, as assessed by peripheral blood oxygenation.-Jung, M.-Y., Kang, J.-H., Hernandez, D. M., Yin, X., Andrianifahanana, M., Wang, Y., Gonzalez-Guerrico, A., Limper, A. H., Lupu, R., Leof, E. B. Fatty acid synthase is required for profibrotic TGF-β signaling.

| S-EPMC5998981 | biostudies-literature

AUD Biomarkers Study (Proteomic and Genomic Analysis of Biospecimens)

Project description:Study purpose: to explore the entire spectrum of proteomic and genomic changes (amongst others) involved in diseases and in healthy/control populations. The Study is designed to discover biomarkers, develop and validate diagnostic assays, instruments and therapeutics as well as other medical research. Specifically, researchers may analyze proteins, RNA, DNA copy number changes, including large and small (1,000-100,000 kb) scale rearrangements, transcription profiles, epigenetic modifications, sequence variation, and sequence in both diseased tissue and case-matched germline DNA from Subjects.

| 62369 | ecrin-mdr-crc

Ursodeoxycholic acid promoted TGF-β degradation

Project description:MS analysis of proteins interacting with PKA and TGF-β1 in HEK293T cells. MS analysis of immunoprecipitated TGF-β1 in HEK293T cells with TGF-β1 overexpression.

2022-06-28 | PXD031801 | Pride

Functional proteomic analysis of advanced serous ovarian cancer using reverse phase protein array: TGF-beta pathway signaling indicates response to primary chemotherapy.

Project description:Using reverse phase protein array, we measured protein expression associated with response to primary chemotherapy in patients with advanced-stage, high-grade serous ovarian cancer.Tumor samples were obtained from 45 patients with advanced high-grade serous cancers from the Gynecology Tumor Bank at the British Columbia Cancer Agency. Treatment consisted of platinum-based chemotherapy following debulking surgery. Protein lysates were prepared from fresh frozen tumor samples, and 80 validated proteins from signaling pathways implicated in ovarian carcinogenesis were measured by reverse phase protein array. Normalization of Ca-125 by the 3rd cycle of chemotherapy was chosen as the primary outcome measure of chemotherapy response. Logistic regression was used for multivariate analysis to identify protein predictors of Ca-125 normalization and Cox regression to test for the association between protein expression and progression-free survival. A significance level of P<or=0.05 was used.The mean age at diagnosis was 56.8 years. epidermal growth factor receptor, YKL-40, and several transforming growth factor beta (TGF-beta) pathway proteins [c-jun-NH2-kinase (JNK), JNK phosphorylated at residues 183 and 185, plasminogen activator inhibitor 1, Smad3, TAZ] showed significant associations with Ca-125 normalization on univariate testing. On multivariate analysis, epidermal growth factor receptor (P<0.02), JNK (P<0.01), and Smad3 (P<0.04) were significantly associated with normalization of Ca-125. Contingency table analysis of pathway-classified proteins revealed that the selection of TGF-beta pathway proteins was unlikely because of false discovery (P<0.007; Bonferroni adjusted).TGF-beta pathway signaling likely plays an important role as a marker or mediator of chemoresistance in advanced serous ovarian cancer. On this basis, future studies to develop and validate a useful predictor of treatment failure are warranted.

| S-EPMC2877659 | biostudies-literature

Targeting TGF-β signaling in cancer.

Project description:IntroductionThe transforming growth factor-β (TGF-β) signaling pathway has a pivotal role in tumor suppression and yet, paradoxically, in tumor promotion. Functional context dependent insights into the TGF-β pathway are crucial in developing TGF-β-based therapeutics for cancer.Areas coveredThis review discusses the molecular mechanism of the TGF-β pathway and describes the different ways of tumor suppression by TGF-β. It is then explained how tumors can evade these effects and how TGF-β contributes to further growing and spreading of some of the tumors. In the last part of the review, the data on targeting TGF-β pathway for cancer treatment is assessed. This review focuses on anti-TGF-β based treatment and other options targeting activated pathways in tumors where the TGF-β tumor suppressor pathway is lost. Pre-clinical as well up to date results of the most recent clinical trials are given.Expert opinionTargeting the TGF-β pathway can be a promising direction in cancer treatment. However, several challenges still exist, the most important are differentiating between the carcinogenic effects of TGF-β and its other physiological roles, and delineating the tumor suppressive versus the tumor promoting roles of TGF-β in each specific tumor. Future studies are needed in order to find safer and more effective TGF-β-based drugs.

| S-EPMC3745214 | biostudies-literature

Proteomics of TGF beta signaling

Project description:HaCaT cells were treated with TGF beta1 for different time points to follw protein and phosphoproteome changes on a temporal scale. Samples were analyzed using a shotgun proteomic approach on a Q exactive coupled to reverse phase HPLC. The measurements resulted in the identification of over 20,000 phopshorylation sites and over 6,000 protein expression profiles.

2014-07-01 | PXD000496 | Pride

Quantitative analysis of the secretome of TGF-beta signaling-deficient mammary fibroblasts.

Project description:Transforming growth factor beta (TGF-beta) is a master regulator of autocrine and paracrine signaling pathways between a tumor and its microenvironment. Decreased expression of TGF-beta type II receptor (TbetaRII) in stromal cells is associated with increased tumor metastasis and shorter patient survival. In this study, SILAC quantitative proteomics was used to identify differentially externalized proteins in the conditioned media from the mammary fibroblasts with or without intact TbetaRII. Over 1000 proteins were identified and their relative differential levels were quantified. Immunoassays were used to further validate identification and quantification of the proteomic results. Differential expression was detected for various extracellular proteins, including proteases and their inhibitors, growth factors, cytokines, and extracellular matrix proteins. CXCL10, a cytokine found to be up-regulated in the TbetaRII knockout mammary fibroblasts, is shown to directly stimulate breast tumor cell proliferation and migration. Overall, this study revealed hundreds of specific extracellular protein changes modulated by deletion of TbetaRII in mammary fibroblasts, which may play important roles in the tumor microenvironment. These results warrant further investigation into the effects of inhibiting the TGF-beta signaling pathway in fibroblasts because systemic inhibition of TGF-beta signaling pathways is being considered as a potential cancer therapy.

| S-EPMC4156855 | biostudies-literature

COVID-19: Immunohistochemical Analysis of TGF-β Signaling Pathways in Pulmonary Fibrosis.

Project description:Acute respiratory distress syndrome (ARDS) followed by repair with lung remodeling is observed in COVID-19. These findings can lead to pulmonary terminal fibrosis, a form of irreversible sequelae. There is evidence that TGF-β is intimately involved in the fibrogenic process. When activated, TGF-β promotes the differentiation of fibroblasts into myofibroblasts and regulates the remodeling of the extracellular matrix (ECM). In this sense, the present study evaluated the histopathological features and immunohistochemical biomarkers (ACE-2, AKT-1, Caveolin-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-β1 tissue expression) involved in the TGF-β1 signaling pathways and pulmonary fibrosis. The study consisted of 24 paraffin lung samples from patients who died of COVID-19 (COVID-19 group), compared to 10 lung samples from patients who died of H1N1pdm09 (H1N1 group) and 11 lung samples from patients who died of different causes, with no lung injury (CONTROL group). In addition to the presence of alveolar septal fibrosis, diffuse alveolar damage (DAD) was found to be significantly increased in the COVID-19 group, associated with a higher density of Collagen I (mature) and III (immature). There was also a significant increase observed in the immunoexpression of tissue biomarkers ACE-2, AKT-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-β1 in the COVID-19 group. A significantly lower expression of Caveolin-1 was also found in this group. The results suggest the participation of TGF-β pathways in the development process of pulmonary fibrosis. Thus, it would be plausible to consider therapy with TGF-β inhibitors in those patients recovered from COVID-19 to mitigate a possible development of pulmonary fibrosis and its consequences for post-COVID-19 life quality.

| S-EPMC8745764 | biostudies-literature

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