Heme Oxygenase-1 Regulates Matrix Metalloproteinase MMP-1 Secretion and Chondrocyte Cell Death via Nox4 NADPH Oxidase Activity in Chondrocytes
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{"title"=>"Heme Oxygenase-1 Regulates Matrix Metalloproteinase MMP-1 Secretion and Chondrocyte Cell Death via Nox4 NADPH Oxidase Activity in Chondrocytes", "type"=>"journal", "authors"=>[{"first_name"=>"Francis", "last_name"=>"Rousset", "scopus_author_id"=>"36638284700"}, {"first_name"=>"Minh Vu Chuong", "last_name"=>"Nguyen", "scopus_author_id"=>"36937670400"}, {"first_name"=>"Laurent", "last_name"=>"Grange", "scopus_author_id"=>"6603059709"}, {"first_name"=>"Françoise", "last_name"=>"Morel", "scopus_author_id"=>"7202882228"}, {"first_name"=>"Bernard", "last_name"=>"Lardy", "scopus_author_id"=>"8517003500"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"369157912", "sgr"=>"84879260319", "issn"=>"19326203", "pmid"=>"23840483", "scopus"=>"2-s2.0-84879260319", "doi"=>"10.1371/journal.pone.0066478", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)"}, "id"=>"4076d846-3664-3dd3-820d-f095bf64ab8d", "abstract"=>"Interleukin-1β (IL-1β) activates the production of reactive oxygen species (ROS) and secretion of MMPs as well as chondrocyte apoptosis. Those events lead to matrix breakdown and are key features of osteoarthritis (OA). We confirmed that in human C-20/A4 chondrocytes the NADPH oxidase Nox4 is the main source of ROS upon IL-1β stimulation. Since heme molecules are essential for the NADPH oxidase maturation and activity, we therefore investigated the consequences of the modulation of Heme oxygenase-1 (HO-1), the limiting enzyme in heme catabolism, on the IL-1β signaling pathway and more specifically on Nox4 activity. Induction of HO-1 expression decreased dramatically Nox4 activity in C-20/A4 and HEK293 T-REx™ Nox4 cell lines. Unexpectedly, this decrease was not accompanied by any change in the expression, the subcellular localization or the maturation of Nox4. In fact, the inhibition of the heme synthesis by succinylacetone rather than heme catabolism by HO-1, led to a confinement of the Nox4/p22(phox) heterodimer in the endoplasmic reticulum with an absence of redox differential spectrum highlighting an incomplete maturation. Therefore, the downregulation of Nox4 activity by HO-1 induction appeared to be mediated by carbon monoxide (CO) generated from the heme degradation process. Interestingly, either HO-1 or CO caused a significant decrease in the expression of MMP-1 and DNA fragmentation of chondrocytes stimulated by IL-1β. These results all together suggest that a modulation of Nox4 activity via heme oxygenase-1 may represent a promising therapeutic tool in osteoarthritis.", "link"=>"http://www.mendeley.com/research/heme-oxygenase1-regulates-matrix-metalloproteinase-mmp1-secretion-chondrocyte-cell-death-via-nox4-na", "reader_count"=>17, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Student > Doctoral Student"=>2, "Researcher"=>2, "Student > Ph. D. Student"=>7, "Other"=>1, "Student > Master"=>1, "Student > Bachelor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Student > Doctoral Student"=>2, "Researcher"=>2, "Student > Ph. D. Student"=>7, "Other"=>1, "Student > Master"=>1, "Student > Bachelor"=>2}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>3, "Agricultural and Biological Sciences"=>9, "Medicine and Dentistry"=>3}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>9}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"Switzerland"=>1}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1095150", "https://ndownloader.figshare.com/files/1095153", "https://ndownloader.figshare.com/files/1095154", "https://ndownloader.figshare.com/files/1095157", "https://ndownloader.figshare.com/files/1095159", "https://ndownloader.figshare.com/files/1095163", "https://ndownloader.figshare.com/files/1095164"], "description"=>"<div><p>Interleukin-1β (IL-1β) activates the production of reactive oxygen species (ROS) and secretion of MMPs as well as chondrocyte apoptosis. Those events lead to matrix breakdown and are key features of osteoarthritis (OA). We confirmed that in human C-20/A4 chondrocytes the NADPH oxidase Nox4 is the main source of ROS upon IL-1β stimulation. Since heme molecules are essential for the NADPH oxidase maturation and activity, we therefore investigated the consequences of the modulation of Heme oxygenase-1 (HO-1), the limiting enzyme in heme catabolism, on the IL-1β signaling pathway and more specifically on Nox4 activity. Induction of HO-1 expression decreased dramatically Nox4 activity in C-20/A4 and HEK293 T-REx™ Nox4 cell lines. Unexpectedly, this decrease was not accompanied by any change in the expression, the subcellular localization or the maturation of Nox4. In fact, the inhibition of the heme synthesis by succinylacetone rather than heme catabolism by HO-1, led to a confinement of the Nox4/p22<sup>phox</sup> heterodimer in the endoplasmic reticulum with an absence of redox differential spectrum highlighting an incomplete maturation. Therefore, the downregulation of Nox4 activity by HO-1 induction appeared to be mediated by carbon monoxide (CO) generated from the heme degradation process. Interestingly, either HO-1 or CO caused a significant decrease in the expression of MMP-1 and DNA fragmentation of chondrocytes stimulated by IL-1β. These results all together suggest that a modulation of Nox4 activity via heme oxygenase-1 may represent a promising therapeutic tool in osteoarthritis.</p></div>", "links"=>[], "tags"=>["Biochemistry", "cytochemistry", "cell membrane", "Extracellular matrix", "metabolism", "Oxygen metabolism", "chemical biology", "enzymes", "immunochemistry", "proteins", "Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "Redox signaling", "Cell death", "Cellular stress responses", "rheumatology", "osteoarthritis", "oxygenase-1", "regulates", "matrix", "metalloproteinase", "mmp-1", "secretion", "chondrocyte", "nox4", "nadph", "oxidase"], "article_id"=>726793, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Francis Rousset", "Minh Vu Chuong Nguyen", "Laurent Grange", "Françoise Morel", "Bernard Lardy"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0066478.s001", "https://dx.doi.org/10.1371/journal.pone.0066478.s002", "https://dx.doi.org/10.1371/journal.pone.0066478.s003", "https://dx.doi.org/10.1371/journal.pone.0066478.s004", "https://dx.doi.org/10.1371/journal.pone.0066478.s005", "https://dx.doi.org/10.1371/journal.pone.0066478.s006", "https://dx.doi.org/10.1371/journal.pone.0066478.s007"], "stats"=>{"downloads"=>3, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Heme_Oxygenase_1_Regulates_Matrix_Metalloproteinase_MMP_1_Secretion_and_Chondrocyte_Cell_Death_via_Nox4_NADPH_Oxidase_Activity_in_Chondrocytes_/726793", "title"=>"Heme Oxygenase-1 Regulates Matrix Metalloproteinase MMP-1 Secretion and Chondrocyte Cell Death via Nox4 NADPH Oxidase Activity in Chondrocytes", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-06-20 01:53:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/1095145"], "description"=>"<p>(<b>A</b>) Tet induced HEK293 T-REx™ Nox4 cells were treated for 1h with 100 µM CORM (a CO donor) or RuCl (the control molecule). Histogram shows the RLU sum obtained from the 45 min kinetic of Nox4 activity from 5×10<sup>5</sup> cells assessed by chemiluminescence. * p<0.05 versus RuCl treated cells. (<b>B</b>) 5×10<sup>5</sup> C-20/A4 chondrocytes were pre-treated for 1 h with 100 µM CORM or RuCl. Nox4 activity was then assessed by chemiluminescence. Results are expressed as percentage of RuCl treated cells. Values represent the mean +/− S.D. of determinations in triplicate obtained the same day. * p<0.05 versus RuCl treated cells. (<b>C</b>) C-20/A4 Nox4A chondrocytes were stimulated with 2 ng/ml IL-1β and treated with 100 µM CORM or the control RuCl for 16 h. Medium supernatant was then collected and concentrated 10 times by centricon. 10 µg of proteins were loaded on 10% SDS-PAGE for MMP-1 immunodetection by Western Blot. Results are representative of three independent experiments.</p>", "links"=>[], "tags"=>["Biochemistry", "cytochemistry", "cell membrane", "Extracellular matrix", "metabolism", "Oxygen metabolism", "chemical biology", "enzymes", "immunochemistry", "proteins", "Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "Redox signaling", "Cell death", "Cellular stress responses", "rheumatology", "osteoarthritis", "monoxide", "decreases", "nox4", "mmp-1"], "article_id"=>726791, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Francis Rousset", "Minh Vu Chuong Nguyen", "Laurent Grange", "Françoise Morel", "Bernard Lardy"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0066478.g006", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Carbon_monoxide_CO_decreases_Nox4_activity_and_MMP_1_expression_/726791", "title"=>"Carbon monoxide (CO) decreases Nox4 activity and MMP-1 expression.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-20 01:53:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/1095144"], "description"=>"<p>(<b>A</b>) Nox4GFP C-20/A4 chondrocytes were treated with 25 µM CoPP-IX or 25 µg/ml SA during 48 h. Cells were then fixed with PFA, permeabilized and p22<sup>phox</sup> was stained with 16G7 mAb antibody (red). The nucleus was stained with Hoechst 33256 (blue). (<b>B</b>) WT and Nox4 chondrocytes were treated or not with succinylacetone (25 µg/ml during 48 h) or were transfected with HO-1. Reduced minus oxidized difference spectra of Nox4 were assessed on 5 mg/ml of proteins from a 1% (v/v) Triton X-100 extracts. The positive control was obtained with cytochrome <i>b</i><sub>558</sub> purified from human neutrophils. (<b>C</b>) Concentration of cytochrome <i>b</i> in the extract was calculated with a ε<sub>426</sub> nm value of 106 mM<sup>−1</sup> cm<sup>−1</sup>.</p>", "links"=>[], "tags"=>["Biochemistry", "cytochemistry", "cell membrane", "Extracellular matrix", "metabolism", "Oxygen metabolism", "chemical biology", "enzymes", "immunochemistry", "proteins", "Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "Redox signaling", "Cell death", "Cellular stress responses", "rheumatology", "osteoarthritis", "heme", "dimer"], "article_id"=>726790, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Francis Rousset", "Minh Vu Chuong Nguyen", "Laurent Grange", "Françoise Morel", "Bernard Lardy"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0066478.g005", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inhibition_of_heme_synthesis_rather_than_heme_catabolism_affects_Nox4_p22_dimer_formation_and_heme_integration_/726790", "title"=>"Inhibition of heme synthesis, rather than heme catabolism, affects Nox4/p22 dimer formation and heme integration.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-20 01:53:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/1095141"], "description"=>"<p>(<b>A</b>) C-20/A4 chondrocytes were treated or not with 10 or 25 µM CoPP-IX for 48 h. Nox4 activity was then measured by chemiluminescence from 5×10<sup>5</sup> WT or Nox4A transfected cells. RLU were recorded every 30 s for 45 min as described in material and methods. * p<0.05 versus untreated Nox4 cells. (<b>B</b>) Similar experiments were also performed on chondrocytes (WT and Nox4A) stably transfected with HO-1 or the empty vector (EV) as described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0066478#s2\" target=\"_blank\">material and methods</a>. Values represent the mean +/− S.D. of three determinations obtained the same day and are representative of three independent experiments. * p<0.05 versus EV Nox4 cells.</p>", "links"=>[], "tags"=>["Biochemistry", "cytochemistry", "cell membrane", "Extracellular matrix", "metabolism", "Oxygen metabolism", "chemical biology", "enzymes", "immunochemistry", "proteins", "Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "Redox signaling", "Cell death", "Cellular stress responses", "rheumatology", "osteoarthritis", "overexpression", "decreases", "nox4"], "article_id"=>726787, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Francis Rousset", "Minh Vu Chuong Nguyen", "Laurent Grange", "Françoise Morel", "Bernard Lardy"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0066478.g002", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HO_1_overexpression_decreases_Nox4_activity_in_C_20_A4_chondrocytes_/726787", "title"=>"HO-1 overexpression decreases Nox4 activity in C-20/A4 chondrocytes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-20 01:53:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/1095140"], "description"=>"<p>(<b>A</b>) Predicted linear domain structure of Nox4A, the functional isoform and Nox4B, deleted for a putative NADPH binding site. (<b>B</b>) ROS production was measured by chemiluminescence on 5×10<sup>5</sup> intact C-20/A4 chondrocytes overexpressing Nox4A or Nox4B treated or not with 5 mM of Tiron. Results are expressed as the sum of all RLU measurements recorded every 30 s during 45 min. Values represent the mean +/− S.D. of four determinations obtained the same day. * p<0.05 versus untreated Nox4A cells. (<b>C</b>) C-20/A4 chondrocytes transfected with genes encoding for Nox4A or Nox4B were stimulated or not with 2 ng/ml IL-1ß with or without 5 mM Tiron. After 48h, supernatant was collected, concentrated 10 times by centricon and 10 µg of proteins were loaded for MMP-1 immunodetection by Western Blot. Results are representative of three independent experiments. (<b>D</b>) C-20/A4 chondrocytes transfected with genes encoding for Nox4A or Nox4B were treated or not with 10 ng/ml IL-1ß. After 5 days, cells were detached and fixed with ice cold absolute ethanol. Cells were then washed twice in PBS and stained with propidium iodide before flow cytometry acquisition. * p<0.05 versus Nox4B cells.</p>", "links"=>[], "tags"=>["Biochemistry", "cytochemistry", "cell membrane", "Extracellular matrix", "metabolism", "Oxygen metabolism", "chemical biology", "enzymes", "immunochemistry", "proteins", "Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "Redox signaling", "Cell death", "Cellular stress responses", "rheumatology", "osteoarthritis", "mediates", "mmp-1", "secretion", "dna", "fragmentation", "chondrocyte"], "article_id"=>726786, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Francis Rousset", "Minh Vu Chuong Nguyen", "Laurent Grange", "Françoise Morel", "Bernard Lardy"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0066478.g001", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Nox4_mediates_IL_1_223_effects_on_MMP_1_secretion_and_DNA_fragmentation_in_C_20_A4_chondrocyte_cells_/726786", "title"=>"Nox4 mediates IL-1ß-effects on MMP-1 secretion and DNA fragmentation in C-20/A4 chondrocyte cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-20 01:53:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/1095143"], "description"=>"<p>(<b>A</b> and <b>B</b>) C-20/A4 Nox4A chondrocytes were transfected with HO-1 encoding vector or the empty vector (EV) ((1) and (2) are from two independent stable transfections) (<b>A</b>) or were treated with 25 µM CoPP-IX or 25 µg/ml SA during 48h (<b>B</b>). Nox4 expression was then assessed by Western Blot with 8E9 antibody on 150 µg of protein from 1% (v/v) Triton X-100 extract. VDAC protein served as loading control. (<b>C</b> and <b>D</b>) Nox4GFP overexpressing C-20/A4 chondrocytes were treated or not with 25 µM CoPP-IX (<b>C</b>) or 25 µg/ml succinylacetone (<b>D</b>) for 48h. (<b>C</b>) Cells were fixed with 4% paraformaldehyde (PFA) and plasma membrane Nox4 was stained with 8E9 mAb before cell permeabilization. Cells were then permeabilized with 0.1% (v/v) Triton X-100 and immunostained for HO-1 (red). Right panels show the 8E9 mAb immunostaining (white arrows) with the nucleus. (<b>D</b>) SA treated Nox4GFP expressing chondrocytes were fixed with 4% PFA and permeabilized with 0.1% (v/v) Triton X-100. Cells were then immunolabelled with calnexin (red) and nucleus was stained with Hoechst 33258 (blue). (<b>E</b> and <b>F</b>) HEK293 T-REx™ cells were induced or not for Nox4 expression with tetracycline (Tet) and for HO-1 with 25 µM CoPP-IX or were treated with 25 µg/ml SA during 48 h. (<b>E</b>) Nox4 expressed at the plasma membrane was stained with 8E9 mAb (recognizing an extracellular epitope of Nox4). Plasma membrane Nox4 expression was then quantified by flow cytometry. Non-induced (NI) cells are displayed in grey solid line, tet-induced cells in black continuous line, tet-induced cells treated by CoPP-IX in black dotted line and tet-induced cells treated with SA in grey continuous line. (<b>F</b>) Total Nox4 expression was assessed by Western Blot with 8E9 antibody on 150 µg of protein from a 1% (v/v) Triton X-100 extract. Actin protein served as loading control. Results are representative of three independent experiments.</p>", "links"=>[], "tags"=>["Biochemistry", "cytochemistry", "cell membrane", "Extracellular matrix", "metabolism", "Oxygen metabolism", "chemical biology", "enzymes", "immunochemistry", "proteins", "Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "Redox signaling", "Cell death", "Cellular stress responses", "rheumatology", "osteoarthritis", "nox4", "subcellular"], "article_id"=>726789, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Francis Rousset", "Minh Vu Chuong Nguyen", "Laurent Grange", "Françoise Morel", "Bernard Lardy"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0066478.g004", "stats"=>{"downloads"=>4, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Heme_availability_does_not_modify_Nox4_total_protein_expression_but_affects_Nox4_subcellular_compartmentation_/726789", "title"=>"Heme availability does not modify Nox4 total protein expression but affects Nox4 subcellular compartmentation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-20 01:53:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1095142"], "description"=>"<p>(<b>A</b> and <b>B</b>) C-20/A4 chondrocytes overexpressing Nox4A or Nox4B were induced or not for HO-1 expression with 10 or 25 µM CoPP-IX for 48h (A). C-20/A4 Nox4A chondrocytes were stably transfected with HMOX1 gene (encoding for HO-1) or the empty vector (EV) (B). Cells were stimulated or not with 2 ng/ml IL-1ß. After 48h, the media supernatant was collected, concentrated 10 times by centricon. 10 µg of proteins were loaded on 10% SDS-PAGE for MMP-1 immunodetection by Western Blot. (<b>C</b>) C-20/A4 Nox4A chondrocytes were treated or not with 10 ng/ml IL-1ß +/−10 µM CoPP-IX for 5 days in DMEM 2% fetal bovine serum. Cells were then washed, fixed with ice cold ethanol, stained with propidium iodide and 5×10<sup>5</sup> cells fluorescence was assessed by FACS. Results are representative of three independent experiments.</p>", "links"=>[], "tags"=>["Biochemistry", "cytochemistry", "cell membrane", "Extracellular matrix", "metabolism", "Oxygen metabolism", "chemical biology", "enzymes", "immunochemistry", "proteins", "Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "Redox signaling", "Cell death", "Cellular stress responses", "rheumatology", "osteoarthritis", "decreases", "mmp-1", "chondrocytes", "dna"], "article_id"=>726788, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Francis Rousset", "Minh Vu Chuong Nguyen", "Laurent Grange", "Françoise Morel", "Bernard Lardy"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0066478.g003", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HO_1_decreases_MMP_1_expression_and_chondrocytes_DNA_fragmentation_/726788", "title"=>"HO-1 decreases MMP-1 expression and chondrocytes DNA fragmentation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-20 01:53:08"}

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Relative Metric

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