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Gerard H. Koppelman - One of the best experts on this subject based on the ideXlab platform.
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IL33 regulates airway neuronal plasticity in vitro
Mechanisms of lung injury and repair, 2020Co-Authors: Pien A. Goldsteen, Gerard H. Koppelman, Martijn C Nawijn, L. Van Der Koog, Loes E. M. Kistemaker, Y. S. Prakash, Benedikt Ditz, M. Van Den Berge, Amalia M. Dolga, Reinoud GosensAbstract:Rationale: In recent years, more evidence has become available showing that airway nerves may undergo remodeling in asthma. The mechanisms involved in this response remain largely unknown. We aimed to assess the role of IL13 and IL33 in neuronal plasticity via secretion of ASM-derived neurotrophic factors (NTFs) such as BDNF and its receptor TrkB. Methods: Primary bovine airway smooth muscle (bASM) or human (hASM) cells were stimulated with IL13 or IL33, either in mono-cultures or in co-cultures with neuronal SH-SY5Y cells. Single-cell RNA seq data from airway biopsies of asthma patients was mined to assess the expression of NTFs and their receptors. Results: IL33 stimulation of bASM/SH-SY5Y and hASM/SH-SY5Y co-cultures increased BDNF expression, whereas IL13 stimulation did not alter BDNF/TrkB expression. IF staining showed an increased neuronal density upon IL33 stimulation in bASM/SH-SY5Y and hASM/SH-SY5Y co-cultures. Inhibiting the IL33 receptor ST2/IL1RL1 abolished the effect, whereas anti-BDNF partially prevented the augmented neuronal network formation. Single-cell seq data from asthma patients indicated TrkB being primarily expressed in ASM and increased in expression in asthmatic donors. Furthermore, in biopsies from asthma patients, a correlation was found between IL33 receptor IL1RL1 and TrkB mRNA expression. Conclusions: IL33 is a potential link between airway inflammation and airway neuronal plasticity, as IL-33 increased BDNF and TrkB expression and neuronal density in vitro. Increased neuronal density could be inhibited by anti-ST2 and is partially mediated via TrkB/BDNF. Importantly, patient data showed a correlation between IL1RL1 and TrkB, suggesting a critical role for IL33 in neuronal plasticity in asthma.
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IL33 receptor activation is IL33 isoform and receptor genotype specific
Molecular pathology and funct. genomics, 2019Co-Authors: Michael A. Portelli, Gerard H. Koppelman, Matthew Edwards, M. Ketelaar, Joshua D. Hoffman, David L. Mayhew, Ian P. Hall, Martijn Nawjin, Antoon J. M. Van OosterhoutAbstract:Introduction: Interleukin 33 (IL33) and its receptor (IL1RL1/ST2) play important roles in asthma development. Multiple IL33 isoforms have been identified, while IL1RL1 contains coding region polymorphisms associated with asthma. Aim: To characterise the ability of IL33 isoforms to activate IL1RL1 signalling and determine the role of IL1RL1 TIR signalling domain haplotypes. Methods: A NFKB/AP1 promoter driven secretory alkaline phosphatase (SEAP) cell line was engineered to express asthma risk or protective IL1RL1 TIR domain haplotype receptors. Cells were treated with recombinant IL33 isoforms (95-270aa, 99-270aa, 102-270aa, 112-270aa, 113-270aa, Exon 3-4 deletion & oxidisation resistant) at 1, 10, 25 & 50ng/ml for 24 hours. Activity was measured by colorimetric assay (SEAP) & ELISA (IL8). Results: All IL33 variants activated IL1RL1, with elevated SEAP/IL8 responses observed in risk haplotype carriers. Only the 99-270aa & oxidisation resistant forms activated the protective haplotype. The two longest isoforms gave the greatest maximal response, while the Exon 3-4 deletion variant had limited activation. Oxidisation resistant IL33 had the largest SEAP signal, but limited IL8 response. Conclusion: The IL1RL1 asthma protective haplotype attenuates IL33 driven inflammation irrespective of isotype. The increased signalling observed for longer IL33 isoforms generated in vivo by proteolytic cleavage via e.g. allergens may be asthma-relevant. The limited activity of the Exon 4-5 deletion suggests a protective role for this variant as a competitive antagonist. Overall, we demonstrate that activation of the IL33/IL1RL1 axis is complex, with response governed by a combination of IL33 isoform and IL1RL1 receptor polymorphisms.
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meQTL analysis of asthma GWAS loci and DNA methylation
European Respiratory Journal, 2016Co-Authors: Ashish Kumar, Simon Kebede Merid, Cheng-jian Xu, Olena Gruzieva, Erik Melen, Juha Kere, Cilla Söderhäll, Gerard H. Koppelman, Goran PershagenAbstract:Background: Asthma is characterized as a chronic inflammation disease and has increased in prevalence over the decades. Genome-wide association studies (GWAS) have implicated several single nucleotide polymorphisms (SNPs) with varying risk estimates for asthma, but the etiology is still not fully understood. Objective: To investigate the association between genetic and epigenetic (methylation) variations in six common GWAS asthma genes - ORMDL3, GSDMB, IL1RL1, IL4R, TSLP and WDR36, we explored the cis and trans-regulatory effects to identify SNPs associated with altered DNA methylation (meQTL) in 500kb buffer region and how top GWAS SNPs relate with resulting SNP-CpG hits. Methods: Using peripheral blood of 231 eight-year-old children with a doctor's diagnosis of asthma ever and 233 controls, from the BAMSE study, DNA methylation was measured on Illumina 450K beadchip and SNPs were assessed on Illumina610-Quad beadchip, imputed on 1000 Genomes reference panels. To identify meQTLs, CpG methylation values were regressed on SNP dosages with sex, asthma status and population stratification eigenvalues as covariates. Results: After applying genome-wide Bonferroni significance thresholds, we had significant SNP-CpG pair hits. The top hits for ORMDL3/GSDMB was cg26162295-rs8081462 (p=4.89x10-50) while LD with GWAS top SNP rs7216389 is r2=0.46. Similarly for IL1RL1, cg09003973-rs11902044 was top hit (p=5.76x10-32) and for TSLP, cg13681701-rs35188965 was top hit (p=4.47x10-71), with no LD to their top GWAS SNPs ( r2
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decoding asthma translating genetic variation in il33 and IL1RL1 into disease pathophysiology
The Journal of Allergy and Clinical Immunology, 2013Co-Authors: Neomi S Grotenboer, Gerard H. Koppelman, M. Ketelaar, Martijn C NawijnAbstract:Asthma is a complex disease that results from the interaction between genetic predisposition and environmental factors. Recently, genome-wide association studies have identified a number of genes that significantly contribute to asthma. Two of these genes, IL33 and IL-1 receptor–like 1 (IL1RL1) , act in one signal transduction pathway. IL33 encodes a cytokine released on damage of cells, whereas IL1RL1 encodes part of the IL-33 receptor complex. Recent progress made in functional studies in human subjects and mouse models of allergic airway disease indicate a central role of IL-33 signaling in driving T H 2 inflammation, which is central to eosinophilic allergic asthma. Here, IL-33 acts on cells of both the adaptive and innate immune systems. Very recently, a novel population of IL-33–responsive innate immune cells, the type 2 innate lymphoid cells, was found to produce hallmark T H 2 cytokines, such as IL-5 and IL-13. The relevance of these cells for asthma is underscored by the identification of retinoic acid–related orphan receptor α (RORA) , the gene encoding the transcription factor critical for their differentiation, as another asthma gene in genome-wide association studies. This review describes the mechanisms through which genetic variation at the IL33 and IL1RL1 loci translates into increased susceptibility for asthma. We propose that genetic variation associated with asthma at the IL33 and IL1RL1 loci can be dissected into independent signals with distinct functional consequences for this pathway that is central to asthma pathogenesis.
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IL1RL1 gene variants and nasopharyngeal IL1RL-a levels are associated with severe RSV bronchiolitis: a multicenter cohort study.
PloS one, 2012Co-Authors: Tina E. Faber, Gerard H. Koppelman, Annemieke Schuurhof, Annelies Vonk, Marije P. Hennus, Jan L. L. Kimpen, Riny Janssen, Louis BontAbstract:Background: Targets for intervention are required for respiratory syncytial virus (RSV) bronchiolitis, a common disease during infancy for which no effective treatment exists. Clinical and genetic studies indicate that IL1RL1 plays an important role in the development and exacerbations of asthma. Human IL1RL1 encodes three isoforms, including soluble IL1RL1-a, that can influence IL33 signalling by modifying inflammatory responses to epithelial damage. We hypothesized that IL1RL1 gene variants and soluble IL1RL1-a are associated with severe RSV bronchiolitis. Methodology/Principal Findings: We studied the association between RSV and 3 selected IL1RL1 single-nucleotide polymorphisms rs1921622, rs11685480 or rs1420101 in 81 ventilated and 384 non-ventilated children under 1 year of age hospitalized with primary RSV bronchiolitis in comparison to 930 healthy controls. Severe RSV infection was defined by need for mechanical ventilation. Furthermore, we examined soluble IL1RL1-a concentration in nasopharyngeal aspirates from children hospitalized with primary RSV bronchiolitis. An association between SNP rs1921622 and disease severity was found at the allele and genotype level (p = 0.011 and p = 0.040, respectively). In hospitalized non-ventilated patients, RSV bronchiolitis was not associated with IL1RL1 genotypes. Median concentrations of soluble IL1RL1-a in nasopharyngeal aspirates were >20-fold higher in ventilated infants when compared to non-ventilated infants with RSV (median [and quartiles] 9,357 [936-15,528] pg/ml vs. 405 [112-1,193] pg/ml respectively; p Conclusions: We found a genetic link between rs1921622 IL1RL1 polymorphism and disease severity in RSV bronchiolitis. The potential biological role of IL1RL1 in the pathogenesis of severe RSV bronchiolitis was further supported by high local concentrations of IL1RL1 in children with most severe disease. We speculate that IL1RL1a modifies epithelial damage mediated inflammatory responses during RSV bronchiolitis and thus may serve as a novel target for intervention to control disease severity.
Michiko K Oyoshi - One of the best experts on this subject based on the ideXlab platform.
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allergic skin sensitization promotes eosinophilic esophagitis through the il 33 basophil axis in mice
The Journal of Allergy and Clinical Immunology, 2016Co-Authors: Nicholas Venturelli, Willem S Lexmond, Asa Ohsaki, Samuel Nurko, Hajime Karasuyama, Edda Fiebiger, Michiko K OyoshiAbstract:Background Eosinophilic esophagitis (EoE) is an allergic inflammatory disorder characterized by accumulation of eosinophils in the esophagus. EoE often coexists with atopic dermatitis, a chronic inflammatory skin disease. The impaired skin barrier in patients with atopic dermatitis has been suggested as an entry point for allergic sensitization that triggers development of EoE. Objective We sought to define the mechanisms whereby epicutaneous sensitization through a disrupted skin barrier induces development of EoE. Methods To elicit experimental EoE, mice were epicutaneously sensitized with ovalbumin (OVA), followed by intranasal OVA challenge. Levels of esophageal mRNA for T H 2 cytokines and the IL-33 receptor IL1RL1 (St2) were measured by using quantitative PCR. Esophageal eosinophil accumulation was assessed by using flow cytometry and hematoxylin and eosin staining. In vivo basophil depletion was achieved with diphtheria toxin treatment of Mcpt8 DTR mice, and animals were repopulated with bone marrow basophils. mRNA analysis of esophageal biopsy specimens from patients with EoE was used to validate our findings in human subjects. Results Epicutaneous sensitization and intranasal challenge of wild-type mice resulted in accumulation of eosinophils and upregulation of T H 2 cytokines and St2 in the esophagus. Disruption of the IL-33–ST2 axis or depletion of basophils reduced these features. Expression of ST2 on basophils was required to accumulate in the esophagus and transfer experimental EoE. Expression of IL1RL1/ST2 mRNA was increased in esophageal biopsy specimens from patients with EoE. Topical OVA application on unstripped skin induced experimental EoE in filaggrin-deficient flaky tail (ft/ft) mice but not in wild-type control or ft/ft.St2 −/− mice. Conclusion Epicutaneous allergic sensitization promotes EoE, and this is critically mediated through the IL-33–ST2–basophil axis.
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Allergic skin sensitization promotes eosinophilic esophagitis through the IL-33–basophil axis in mice
The Journal of allergy and clinical immunology, 2016Co-Authors: Nicholas Venturelli, Willem S Lexmond, Asa Ohsaki, Samuel Nurko, Hajime Karasuyama, Edda Fiebiger, Michiko K OyoshiAbstract:Background Eosinophilic esophagitis (EoE) is an allergic inflammatory disorder characterized by accumulation of eosinophils in the esophagus. EoE often coexists with atopic dermatitis, a chronic inflammatory skin disease. The impaired skin barrier in patients with atopic dermatitis has been suggested as an entry point for allergic sensitization that triggers development of EoE. Objective We sought to define the mechanisms whereby epicutaneous sensitization through a disrupted skin barrier induces development of EoE. Methods To elicit experimental EoE, mice were epicutaneously sensitized with ovalbumin (OVA), followed by intranasal OVA challenge. Levels of esophageal mRNA for T H 2 cytokines and the IL-33 receptor IL1RL1 (St2) were measured by using quantitative PCR. Esophageal eosinophil accumulation was assessed by using flow cytometry and hematoxylin and eosin staining. In vivo basophil depletion was achieved with diphtheria toxin treatment of Mcpt8 DTR mice, and animals were repopulated with bone marrow basophils. mRNA analysis of esophageal biopsy specimens from patients with EoE was used to validate our findings in human subjects. Results Epicutaneous sensitization and intranasal challenge of wild-type mice resulted in accumulation of eosinophils and upregulation of T H 2 cytokines and St2 in the esophagus. Disruption of the IL-33–ST2 axis or depletion of basophils reduced these features. Expression of ST2 on basophils was required to accumulate in the esophagus and transfer experimental EoE. Expression of IL1RL1/ST2 mRNA was increased in esophageal biopsy specimens from patients with EoE. Topical OVA application on unstripped skin induced experimental EoE in filaggrin-deficient flaky tail (ft/ft) mice but not in wild-type control or ft/ft.St2 −/− mice. Conclusion Epicutaneous allergic sensitization promotes EoE, and this is critically mediated through the IL-33–ST2–basophil axis.
Song Ho Chang - One of the best experts on this subject based on the ideXlab platform.
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transcription factor hes1 modulates osteoarthritis development in cooperation with calcium calmodulin dependent protein kinase 2
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Shurei Sugita, Keita Okada, Tomotake Okuma, Yoshifumi Mori, Yoko Hosaka, Yuki Taniguchi, Fumiko Yano, Daisuke Mori, Hiroshi Kobayashi, Song Ho ChangAbstract:Notch signaling modulates skeletal formation and pathogenesis of osteoarthritis (OA) through induction of catabolic factors. Here we examined roles of Hes1, a transcription factor and important target of Notch signaling, in these processes. SRY-box containing gene 9 (Sox9)-Cre mice were mated with Hes1fl/fl mice to generate tissue-specific deletion of Hes1 from chondroprogenitor cells; this deletion caused no obvious abnormality in the perinatal period. Notably, OA development was suppressed when Hes1 was deleted from articular cartilage after skeletal growth in type II collagen (Col2a1)-CreERT;Hes1fl/fl mice. In cultured chondrocytes, Hes1 induced metallopeptidase with thrombospondin type 1 motif, 5 (Adamts5) and matrix metalloproteinase-13 (Mmp13), which are catabolic enzymes that break down cartilage matrix. ChIP-seq and luciferase assays identified Hes1-responsive regions in intronic sites of both genes; the region in the ADAMTS5 gene contained a typical consensus sequence for Hes1 binding, whereas that in the MMP13 gene did not. Additionally, microarray analysis, together with the ChIP-seq, revealed novel Hes1 target genes, including Il6 and IL1RL1, coding a receptor for IL-33. We further identified calcium/calmodulin-dependent protein kinase 2δ (CaMK2δ) as a cofactor of Hes1; CaMK2δ was activated during OA development, formed a protein complex with Hes1, and switched it from a transcriptional repressor to a transcriptional activator to induce cartilage catabolic factors. Therefore, Hes1 cooperated with CaMK2δ to modulate OA pathogenesis through induction of catabolic factors, including Adamts5, Mmp13, Il6, and IL1RL1. Our findings have contributed to further understanding of the molecular pathophysiology of OA, and may provide the basis for development of novel treatments for joint disorders.
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Transcription factor Hes1 modulates osteoarthritis development in cooperation with calcium/calmodulin-dependent protein kinase 2.
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Shurei Sugita, Keita Okada, Tomotake Okuma, Yoshifumi Mori, Yoko Hosaka, Yuki Taniguchi, Fumiko Yano, Daisuke Mori, Hiroshi Kobayashi, Song Ho ChangAbstract:Notch signaling modulates skeletal formation and pathogenesis of osteoarthritis (OA) through induction of catabolic factors. Here we examined roles of Hes1, a transcription factor and important target of Notch signaling, in these processes. SRY-box containing gene 9 (Sox9)-Cre mice were mated with Hes1fl/fl mice to generate tissue-specific deletion of Hes1 from chondroprogenitor cells; this deletion caused no obvious abnormality in the perinatal period. Notably, OA development was suppressed when Hes1 was deleted from articular cartilage after skeletal growth in type II collagen (Col2a1)-CreERT;Hes1fl/fl mice. In cultured chondrocytes, Hes1 induced metallopeptidase with thrombospondin type 1 motif, 5 (Adamts5) and matrix metalloproteinase-13 (Mmp13), which are catabolic enzymes that break down cartilage matrix. ChIP-seq and luciferase assays identified Hes1-responsive regions in intronic sites of both genes; the region in the ADAMTS5 gene contained a typical consensus sequence for Hes1 binding, whereas that in the MMP13 gene did not. Additionally, microarray analysis, together with the ChIP-seq, revealed novel Hes1 target genes, including Il6 and IL1RL1, coding a receptor for IL-33. We further identified calcium/calmodulin-dependent protein kinase 2δ (CaMK2δ) as a cofactor of Hes1; CaMK2δ was activated during OA development, formed a protein complex with Hes1, and switched it from a transcriptional repressor to a transcriptional activator to induce cartilage catabolic factors. Therefore, Hes1 cooperated with CaMK2δ to modulate OA pathogenesis through induction of catabolic factors, including Adamts5, Mmp13, Il6, and IL1RL1. Our findings have contributed to further understanding of the molecular pathophysiology of OA, and may provide the basis for development of novel treatments for joint disorders.
Hideoki Ogawa - One of the best experts on this subject based on the ideXlab platform.
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gata2 is a critical transactivator for the human IL1RL1 st2 promoter in mast cells basophils opposing roles for gata2 and gata1 in human IL1RL1 st2 gene expression
Journal of Biological Chemistry, 2012Co-Authors: Yosuke Baba, Keiko Maeda, Takuya Yashiro, Eisuke Inage, Kazumi Kasakura, Ryuyo Suzuki, Francois Niyonsaba, Mutsuko Hara, Atsushi Tanabe, Hideoki OgawaAbstract:The IL1RL1/ST2 gene encodes a receptor for IL-33. Signaling from IL1RL1/ST2 induced by IL-33 binding was recently identified as a modulator of the Th2 response. The target cells for IL-33 are restricted in some hematopoietic lineages, including mast cells, basophils, eosinophils, Th2 cells, natural killer cells, and dendritic cells. To clarify the molecular mechanisms of cell type-specific IL1RL1/ST2 expression in mast cells and basophils, transcriptional regulation of the human IL1RL1/ST2 promoter was investigated using the mast cell line LAD2 and the basophilic cell line KU812. Reporter assays suggested that two GATA motifs just upstream of the transcription start site in the ST2 promoter are critical for transcriptional activity. These two GATA motifs possess the capacity to bind GATA1 and GATA2 in EMSA. ChIP assay showed that GATA2, but not GATA1, bound to the ST2 promoter in LAD2 cells and that histone H3 at the ST2 promoter was acetylated in LAD2 cells, whereas binding of GATA1 and GATA2 to the ST2 promoter was detected in KU812 cells. Knockdown of GATA2 mRNA by siRNA reduced ST2 mRNA levels in KU812 and LAD2 cells and ST2 protein levels in LAD2 cells; in contrast, GATA1 siRNA transfection up-regulated ST2 mRNA levels in KU812 cells. The ST2 promoter was transactivated by GATA2 and repressed by GATA1 in coexpression analysis. When these siRNAs were introduced into human peripheral blood basophils, GATA2 siRNA reduced ST2 mRNA, whereas GATA1 siRNA up-regulated ST2 mRNA. These results indicate that GATA2 and GATA1 positively and negatively control human ST2 gene transcription, respectively.
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GATA2 Is a Critical Transactivator for the Human IL1RL1/ST2 Promoter in Mast Cells/Basophils OPPOSING ROLES FOR GATA2 and GATA1 IN HUMAN IL1RL1/ST2 GENE EXPRESSION
The Journal of biological chemistry, 2012Co-Authors: Yosuke Baba, Keiko Maeda, Takuya Yashiro, Eisuke Inage, Kazumi Kasakura, Ryuyo Suzuki, Francois Niyonsaba, Mutsuko Hara, Atsushi Tanabe, Hideoki OgawaAbstract:The IL1RL1/ST2 gene encodes a receptor for IL-33. Signaling from IL1RL1/ST2 induced by IL-33 binding was recently identified as a modulator of the Th2 response. The target cells for IL-33 are restricted in some hematopoietic lineages, including mast cells, basophils, eosinophils, Th2 cells, natural killer cells, and dendritic cells. To clarify the molecular mechanisms of cell type-specific IL1RL1/ST2 expression in mast cells and basophils, transcriptional regulation of the human IL1RL1/ST2 promoter was investigated using the mast cell line LAD2 and the basophilic cell line KU812. Reporter assays suggested that two GATA motifs just upstream of the transcription start site in the ST2 promoter are critical for transcriptional activity. These two GATA motifs possess the capacity to bind GATA1 and GATA2 in EMSA. ChIP assay showed that GATA2, but not GATA1, bound to the ST2 promoter in LAD2 cells and that histone H3 at the ST2 promoter was acetylated in LAD2 cells, whereas binding of GATA1 and GATA2 to the ST2 promoter was detected in KU812 cells. Knockdown of GATA2 mRNA by siRNA reduced ST2 mRNA levels in KU812 and LAD2 cells and ST2 protein levels in LAD2 cells; in contrast, GATA1 siRNA transfection up-regulated ST2 mRNA levels in KU812 cells. The ST2 promoter was transactivated by GATA2 and repressed by GATA1 in coexpression analysis. When these siRNAs were introduced into human peripheral blood basophils, GATA2 siRNA reduced ST2 mRNA, whereas GATA1 siRNA up-regulated ST2 mRNA. These results indicate that GATA2 and GATA1 positively and negatively control human ST2 gene transcription, respectively.
Shurei Sugita - One of the best experts on this subject based on the ideXlab platform.
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transcription factor hes1 modulates osteoarthritis development in cooperation with calcium calmodulin dependent protein kinase 2
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Shurei Sugita, Keita Okada, Tomotake Okuma, Yoshifumi Mori, Yoko Hosaka, Yuki Taniguchi, Fumiko Yano, Daisuke Mori, Hiroshi Kobayashi, Song Ho ChangAbstract:Notch signaling modulates skeletal formation and pathogenesis of osteoarthritis (OA) through induction of catabolic factors. Here we examined roles of Hes1, a transcription factor and important target of Notch signaling, in these processes. SRY-box containing gene 9 (Sox9)-Cre mice were mated with Hes1fl/fl mice to generate tissue-specific deletion of Hes1 from chondroprogenitor cells; this deletion caused no obvious abnormality in the perinatal period. Notably, OA development was suppressed when Hes1 was deleted from articular cartilage after skeletal growth in type II collagen (Col2a1)-CreERT;Hes1fl/fl mice. In cultured chondrocytes, Hes1 induced metallopeptidase with thrombospondin type 1 motif, 5 (Adamts5) and matrix metalloproteinase-13 (Mmp13), which are catabolic enzymes that break down cartilage matrix. ChIP-seq and luciferase assays identified Hes1-responsive regions in intronic sites of both genes; the region in the ADAMTS5 gene contained a typical consensus sequence for Hes1 binding, whereas that in the MMP13 gene did not. Additionally, microarray analysis, together with the ChIP-seq, revealed novel Hes1 target genes, including Il6 and IL1RL1, coding a receptor for IL-33. We further identified calcium/calmodulin-dependent protein kinase 2δ (CaMK2δ) as a cofactor of Hes1; CaMK2δ was activated during OA development, formed a protein complex with Hes1, and switched it from a transcriptional repressor to a transcriptional activator to induce cartilage catabolic factors. Therefore, Hes1 cooperated with CaMK2δ to modulate OA pathogenesis through induction of catabolic factors, including Adamts5, Mmp13, Il6, and IL1RL1. Our findings have contributed to further understanding of the molecular pathophysiology of OA, and may provide the basis for development of novel treatments for joint disorders.
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Transcription factor Hes1 modulates osteoarthritis development in cooperation with calcium/calmodulin-dependent protein kinase 2.
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Shurei Sugita, Keita Okada, Tomotake Okuma, Yoshifumi Mori, Yoko Hosaka, Yuki Taniguchi, Fumiko Yano, Daisuke Mori, Hiroshi Kobayashi, Song Ho ChangAbstract:Notch signaling modulates skeletal formation and pathogenesis of osteoarthritis (OA) through induction of catabolic factors. Here we examined roles of Hes1, a transcription factor and important target of Notch signaling, in these processes. SRY-box containing gene 9 (Sox9)-Cre mice were mated with Hes1fl/fl mice to generate tissue-specific deletion of Hes1 from chondroprogenitor cells; this deletion caused no obvious abnormality in the perinatal period. Notably, OA development was suppressed when Hes1 was deleted from articular cartilage after skeletal growth in type II collagen (Col2a1)-CreERT;Hes1fl/fl mice. In cultured chondrocytes, Hes1 induced metallopeptidase with thrombospondin type 1 motif, 5 (Adamts5) and matrix metalloproteinase-13 (Mmp13), which are catabolic enzymes that break down cartilage matrix. ChIP-seq and luciferase assays identified Hes1-responsive regions in intronic sites of both genes; the region in the ADAMTS5 gene contained a typical consensus sequence for Hes1 binding, whereas that in the MMP13 gene did not. Additionally, microarray analysis, together with the ChIP-seq, revealed novel Hes1 target genes, including Il6 and IL1RL1, coding a receptor for IL-33. We further identified calcium/calmodulin-dependent protein kinase 2δ (CaMK2δ) as a cofactor of Hes1; CaMK2δ was activated during OA development, formed a protein complex with Hes1, and switched it from a transcriptional repressor to a transcriptional activator to induce cartilage catabolic factors. Therefore, Hes1 cooperated with CaMK2δ to modulate OA pathogenesis through induction of catabolic factors, including Adamts5, Mmp13, Il6, and IL1RL1. Our findings have contributed to further understanding of the molecular pathophysiology of OA, and may provide the basis for development of novel treatments for joint disorders.
