title: Inflammatory conditions partly impair the mechanically mediated activation of Smad2/3 signaling in articular cartilage.
abstract: Joint trauma, which is frequently related with mechanical overloading of articular cartilage, is a well-established risk for osteoarthritis (OA) development. Additionally, reports show that trauma leads to synovial joint inflammation. In consequence, after joint trauma, cartilage is influenced by deleterious excessive loading combined with the catabolic activity of proinflammatory mediators. Since the activation of TGF-β signaling by loading is considered to be a key regulatory pathway for maintaining cartilage homeostasis, we tested the effect of proinflammatory conditions on mechanically mediated activation of TGF-β/Smad2/3P signaling in cartilage.
  
  
  
  Cartilage explants were subjected to dynamic mechanical compression in the presence of interleukin-1 beta (IL-1β) or osteoarthritic synovium-conditioned medium (OAS-CM). Subsequently, the activation of the Smad2/3P pathway was monitored with QPCR analysis of reporter genes and additionally the expression of receptors activating the Smad2/3P pathway was analyzed. Finally, the ability for mechanically mediated activation of Smad2/3P was tested in human OA cartilage.
  
  
  
  IL-1β presence during compression did not impair the upregulation of Smad2/3P reporter genes, however the results were affected by IL-1β-mediated upregulations in unloaded controls. OAS-CM significantly impaired the compression-mediated upregulation of bSmad7 and Tgbfb1. IL-1β suppressed the compression-mediated bAlk5 upregulation where 12 MPa compression applied in the presence of OAS-CM downregulated the bTgfbr2. Mechanically driven upregulation of Smad2/3P reporter genes was present in OA cartilage.
  
  
  
  Proinflammatory conditions partly impair the mechanically mediated activation of the protective TGF-β/Smad2/3P pathway. Additionally, the excessive mechanical compression, applied in the presence of proinflammatory conditions diminishes the expression of the type II TGF-β receptor, a receptor critical for maintenance of articular cartilage.
authors.affiliation: Orthopedic Research Laboratory, Radboud University Medical Center, Geert Grooteplein-Zuid 10, route 547, 6525, GA, Nijmegen, The Netherlands.|Experimental Rheumatology, Radboud University Medical Center, Geert Grooteplein 26-28, route 272, 6525, GA, Nijmegen, The Netherlands.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Madej
authors.affiliation: Orthopedic Research Laboratory, Radboud University Medical Center, Geert Grooteplein-Zuid 10, route 547, 6525, GA, Nijmegen, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Buma
authors.affiliation: Experimental Rheumatology, Radboud University Medical Center, Geert Grooteplein 26-28, route 272, 6525, GA, Nijmegen, The Netherlands. Peter.vanderKraan@radboudumc.nl.
authors.forename: Peter
authors.initials: P
authors.lastname: van der Kraan
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D002417:Cattle; D019902:Chondrocytes / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D009924:Organ Culture Techniques; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D051785:Smad Proteins / Q000378:metabolism*; D013314:Stress, Mechanical; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D051785:Smad Proteins; D016212:Transforming Growth Factor beta
keywords: Cartilage; Dynamic mechanical compression; Inflammation; Osteoarthritis; Transforming growth factor beta