title: Expression of TGFβ-family signalling components in ageing cartilage: age-related loss of TGFβ and BMP receptors.
abstract: Ageing is the main risk factor for osteoarthritis (OA). We investigated if expression of transforming growth factor β (TGFβ)-family components, a family which is crucial for the maintenance of healthy articular cartilage, is altered during ageing in cartilage. Moreover, we investigated the functional significance of selected age-related changes.
  
  
  
  Age-related changes in expression of TGFβ-family members were analysed by quantitative PCR in healthy articular cartilage obtained from 42 cows (age: ¾-10 years). To obtain functional insight of selected changes, cartilage explants were stimulated with TGFβ1 or bone morphogenetic protein (BMP) 9, and TGFβ1 and BMP response genes were measured.
  
  
  
  Age-related cartilage thinning and loss of collagen type 2a1 expression (∼256-fold) was observed, validating our data set for studying ageing in cartilage. Expression of the TGFβ-family type I receptors; bAlk2, bAlk3, bAlk4 and bAlk5 dropped significantly with advancing age, whereas bAlk1 expression did not. Of the type II receptors, expression of bBmpr2 decreased significantly. Type III receptor expression was unaffected by ageing. Expression of the ligands bTgfb1 and bGdf5 also decreased with age. In explants, an age-related decrease in TGFβ1-response was observed for the pSmad3-dependent gene bSerpine1 (P = 0.016). In contrast, ageing did not affect BMP9 signalling, an Alk1 ligand, as measured by expression of the pSmad1/5 dependent gene bId1.
  
  
  
  Ageing negatively affects both the TGFβ-ALK5 and BMP-BMPR signalling routes, and aged chondrocytes display a lowered pSmad3-dependent response to TGFβ1. Because pSmad3 signalling is essential for cartilage homeostasis, we propose that this change contributes to OA development.
authors.affiliation: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: van Caam
authors.affiliation: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands; Orthopaedics Research Lab, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: Madej
authors.affiliation: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Thijssen
authors.affiliation: Department of Molecular Cell Biology and Cancer Genomics Centre Netherlands, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Garcia de Vinuesa
authors.affiliation: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: van den Berg
authors.affiliation: Department of Molecular Cell Biology and Cancer Genomics Centre Netherlands, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: M-J
authors.initials: MJ
authors.lastname: Goumans
authors.affiliation: Department of Molecular Cell Biology and Cancer Genomics Centre Netherlands, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Ten Dijke
authors.affiliation: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Blaney Davidson
authors.affiliation: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Peter.vanderkraan@radboudumc.nl.
authors.forename: P M
authors.initials: PM
authors.lastname: van der Kraan
mesh_terms: D000375:Aging; D000818:Animals; D052004:Bone Morphogenetic Protein Receptors; D002358:Cartilage, Articular; D002417:Cattle; D019902:Chondrocytes; D015398:Signal Transduction; D016212:Transforming Growth Factor beta
chemical_list: D016212:Transforming Growth Factor beta; D052004:Bone Morphogenetic Protein Receptors
keywords: Ageing; BMP receptors; Cartilage; Smad; TGFβ receptors