title: Ageing is associated with reduction of mechanically-induced activation of Smad2/3P signaling in articular cartilage.
abstract: OBJECTIVE
  Mechanical signals control key cellular processes in articular cartilage. Previously we have shown that mechanical compression is an important ALK5/Smad2/3P activator in cartilage explants. However, age-related changes in the cartilage are known to affect tissue mechanosensitivity and also ALK5/Smad2/3P signaling. We have investigated whether ageing of cartilage is associated with an altered response to mechanical compression.
  
  
  METHODS
  Articular cartilage explants of two different age groups (young-6-36 months old, aged-6 - 13 years old) were subjected to dynamic mechanical compression with 3 MPa (physiological) or 12 MPa (excessive) load. Subsequently, essential cartilage extracellular matrix (ECM) components and tissue growth factors gene expression was measured in young and aged cartilage by QPCR. Furthermore, the ability of young and aged cartilage, to activate the Smad2/3P signaling in response to compression was analyzed and compared. This was done by immunohistochemical (IH) Smad2P detection and Smad3-responsive gene expression analysis.
  
  
  RESULTS
  Aged cartilage showed a highly reduced capacity for mechanically-mediated activation of Smad2/3P signaling when compared to young cartilage. Compression of aged cartilage, induced collagen type II (Col2a1) and fibronectin (Fn1) expression to a far lesser extent than in young cartilage. Additionally, in aged cartilage no mechanically mediated up-regulation of bone morphogenetic protein 2 (Bmp2) and connective tissue growth factor (Ctgf) was observed.
  
  
  CONCLUSIONS
  We identified age-related changes in cellular responses to mechanical stimulation of articular cartilage. We propose that these changes might be associated with age-related alterations in cartilage functioning and can underlie mechanisms for development of age-related cartilage diseases like osteoarthritis (OA).
authors.affiliation: Orthopaedic Research Laboratory, Radboudumc, Nijmegen, The Netherlands; Experimental Rheumatology, Radboudumc, Nijmegen, The Netherlands. Electronic address: Wojciech.Madej@radboudumc.nl.
authors.forename: W
authors.initials: W
authors.lastname: Madej
authors.affiliation: Experimental Rheumatology, Radboudumc, Nijmegen, The Netherlands. Electronic address: Arjan.vanCaam@radboudumc.nl.
authors.forename: A
authors.initials: A
authors.lastname: van Caam
authors.affiliation: Experimental Rheumatology, Radboudumc, Nijmegen, The Netherlands. Electronic address: Esmeralda.BlaneyDavidson@radboudumc.nl.
authors.forename: E N Blaney
authors.initials: EN
authors.lastname: Davidson
authors.affiliation: Orthopaedic Research Laboratory, Radboudumc, Nijmegen, The Netherlands. Electronic address: Gerjon.Hannink@radboudumc.nl.
authors.forename: G
authors.initials: G
authors.lastname: Hannink
authors.affiliation: Orthopaedic Research Laboratory, Radboudumc, Nijmegen, The Netherlands. Electronic address: Pieter.Buma@radboudumc.nl.
authors.forename: P
authors.initials: P
authors.lastname: Buma
authors.affiliation: Experimental Rheumatology, Radboudumc, Nijmegen, The Netherlands. Electronic address: Peter.vanderKraan@radboudumc.nl.
authors.forename: P M
authors.initials: PM
authors.lastname: van der Kraan
mesh_terms: D053674:Aggrecans / Q000235:genetics / Q000378:metabolism; D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D002358:Cartilage, Articular / Q000378:metabolism* / Q000502:physiology; D002417:Cattle; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D005109:Extracellular Matrix; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics / Q000378:metabolism; D010003:Osteoarthritis / Q000235:genetics* / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D011312:Pressure; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics* / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D053674:Aggrecans; D055396:Bone Morphogenetic Protein 2; D024043:Collagen Type II; D005353:Fibronectins; D019812:Heparan Sulfate Proteoglycans; D017395:Plasminogen Activator Inhibitor 1; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; C071927:perlecan; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I
keywords: Ageing; Cartilage; Mechanosensitivity; Signal transduction; Smad2/3P signaling; TGF-beta