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10.1186/s13075-017-1302-4 http://scihub22266oqcxt.onion/10.1186/s13075-017-1302-4 C5452635!5452635 !28569204     free     free     free Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 298.79999999999995 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 298.79999999999995 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\28569204 .jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117       Arthritis+Res+Ther 2017 ; 19 (1 ): 112 Nephropedia Template TP {{tp|p=28569204 |t=2017. TGF?1-induced SMAD2/3 and SMAD1/5 phosphorylation are both ALK5-kinase-dependent in primary chondrocytes and mediated by TAK1 kinase activity |pdf=|usr=}}{{28569204 }} gab.com Text TGF 1-induced SMAD2/3 and SMAD1/5 phosphorylation are both ALK5-kinase-dependent in primary chondrocytes and mediated by TAK1 kinase activity JO: Arthritis Res Ther http://www.kidney.de/pget.php?&tw=1&pmid=28569204 #FOAvip BACKGROUND: Dysregulated transforming growth factor ? (TGF?) signaling is implicated in osteoarthritis development, making normalizing TGF? signaling a possible therapy. Theoretically, this can be achieved with small molecule inhibitors specifically targeting the various TGF? receptors and downstream mediators. In this study we explore in primary chondrocytes the use of small molecule inhibitors to target TGF?-induced pSmad1/5/9-, pSmad2/3- and TGF?-activated kinase 1 (TAK1)-dependent signaling. METHOD: Primary bovine chondrocytes and explants were isolated from metacarpophalangeal joints. To modulate TGF? signaling the activin receptor-like kinase (ALK)1/2/3/6 inhibitor LDN-193189, the ALK4/5/7 inhibitor SB-505124 and the TAK1 inhibitor (5Z)-7-Oxozeaenol were used. pSmad1/5 and pSmad2 were measured using western blot analysis and TGF?1-induced gene expression was measured using quantitative real time PCR (qPCR). RESULTS: In chondrocytes, TGF?1 strongly induced both pSmad1/5 and pSmad2. Remarkably, LDN-193189 did not inhibit TGF?-induced pSmad1/5. In contrast, SB-505124 did inhibit both TGF?-induced Smad2 and Smad1/5 phosphorylation. Furthermore, (5Z)-7-Oxozeaenol also profoundly inhibited TGF?-induced pSmad2 and pSmad1/5. Importantly, both SB-505124 and (5Z)-7-Oxozeaenol did not significantly inhibit constitutively active ALK1, making an off-target effect unlikely. Additionally, LDN-193189 was able to potently inhibit BMP2/7/9-induced pSmad1/5, showing its functionality. On gene expression, LDN-193189 did not affect TGF?1-induced regulation, whereas both SB-505124 and (5Z)-7-Oxozeaenol did. Similar results were obtained in cartilage explants, although pSmad1/5 was not strongly induced by addition of TGF?1. CONCLUSION: Our data suggest that ALK5 kinase activity plays a central role in both TGF?-induced Smad1/5 and Smad2/3 phosphorylation, making it difficult to separate both pathways with the use of currently available small molecule inhibitors. Furthermore, our data regarding (5Z)-7-Oxozeaenol suggest that TAK1 facilitates Smad-dependent signaling. Twit Text FOAVip TGF 1-induced SMAD2/3 and SMAD1/5 phosphorylation are both ALK5-kinase-dependent in primary chondrocytes and mediated by TAK1 kinase activity ????Arthritis Res Ther http://www.kidney.de/pget.php?&tw=1&pmid=28569204 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=28569204 #FOAvip English Wikipedia <ref>{{Cite pmid|28569204 }}</ref> TGF?1-induced SMAD2/3 and SMAD1/5 phosphorylation are both ALK5-kinase-dependent in primary chondrocytes and mediated by TAK1 kinase activity #MMPMID28569204 van Caam A ; Madej W ; Garcia de Vinuesa A ; Goumans MJ ; Ten Dijke P ; Blaney Davidson E ; van der Kraan P Arthritis Res Ther 2017[May]; 19 (1 ): 112 PMID28569204 show ga BACKGROUND: Dysregulated transforming growth factor ? (TGF?) signaling is implicated in osteoarthritis development, making normalizing TGF? signaling a possible therapy. Theoretically, this can be achieved with small molecule inhibitors specifically targeting the various TGF? receptors and downstream mediators. In this study we explore in primary chondrocytes the use of small molecule inhibitors to target TGF?-induced pSmad1/5/9-, pSmad2/3- and TGF?-activated kinase 1 (TAK1)-dependent signaling. METHOD: Primary bovine chondrocytes and explants were isolated from metacarpophalangeal joints. To modulate TGF? signaling the activin receptor-like kinase (ALK)1/2/3/6 inhibitor LDN-193189, the ALK4/5/7 inhibitor SB-505124 and the TAK1 inhibitor (5Z)-7-Oxozeaenol were used. pSmad1/5 and pSmad2 were measured using western blot analysis and TGF?1-induced gene expression was measured using quantitative real time PCR (qPCR). RESULTS: In chondrocytes, TGF?1 strongly induced both pSmad1/5 and pSmad2. Remarkably, LDN-193189 did not inhibit TGF?-induced pSmad1/5. In contrast, SB-505124 did inhibit both TGF?-induced Smad2 and Smad1/5 phosphorylation. Furthermore, (5Z)-7-Oxozeaenol also profoundly inhibited TGF?-induced pSmad2 and pSmad1/5. Importantly, both SB-505124 and (5Z)-7-Oxozeaenol did not significantly inhibit constitutively active ALK1, making an off-target effect unlikely. Additionally, LDN-193189 was able to potently inhibit BMP2/7/9-induced pSmad1/5, showing its functionality. On gene expression, LDN-193189 did not affect TGF?1-induced regulation, whereas both SB-505124 and (5Z)-7-Oxozeaenol did. Similar results were obtained in cartilage explants, although pSmad1/5 was not strongly induced by addition of TGF?1. CONCLUSION: Our data suggest that ALK5 kinase activity plays a central role in both TGF?-induced Smad1/5 and Smad2/3 phosphorylation, making it difficult to separate both pathways with the use of currently available small molecule inhibitors. Furthermore, our data regarding (5Z)-7-Oxozeaenol suggest that TAK1 facilitates Smad-dependent signaling. |Animals [MESH] |Benzodioxoles/pharmacology [MESH] |Cattle [MESH] |Chondrocytes/drug effects/*metabolism [MESH] |Enzyme Inhibitors/*pharmacology [MESH] |Imidazoles/pharmacology [MESH] |MAP Kinase Kinase Kinases/*metabolism [MESH] |Osteoarthritis/*metabolism [MESH] |Phosphorylation [MESH] |Protein Serine-Threonine Kinases/*metabolism [MESH] |Pyrazoles/pharmacology [MESH] |Pyridines/pharmacology [MESH] |Pyrimidines/pharmacology [MESH] |Receptor, Transforming Growth Factor-beta Type I [MESH] |Receptors, Transforming Growth Factor beta/*metabolism [MESH] |Smad Proteins/*metabolism [MESH] |Transforming Growth Factor beta1/metabolism [MESH]TGF?1-induced SMAD2/3 and SMAD1/5 phosphorylation are both ALK5-kinase(epmc).pdf DeepDyve Pubget Overpricing