title: The relationship between fibrogenic TGFβ1 signaling in the joint and cartilage degradation in post-injury osteoarthritis.
abstract: OBJECTIVE
  To review the literature on modulation of chondrocyte activities in the osteoarthritic joint, and to discuss these changes in relation to established hard and soft tissue repair paradigms, with an emphasis on transforming growth factor beta (TGFβ1)-mediated signaling which can promote either a chondrogenic or fibrogenic phenotype.
  
  
  METHODS
  Papers addressing the close relationship between repair in general, and the specific post-injury response of joint tissues are summarized. Different interpretations of the role of TGFβ1 in the emergence of an "osteoarthritic" chondrocyte are compared and the phenotypic plasticity of "reparative" progenitor cells is examined. Lastly, emerging data on a central role for A-Disintegrin-And-Metalloproteinase-with-Thrombospondin-like-Sequences-5 (ADAMTS5) activity in modulating TGFβ1 signaling through activin receptor-like kinase 1 (ALK1) and activin receptor-like kinase 5 (ALK5) pathways is discussed.
  
  
  RESULTS
  The review illustrates how a transition from ALK5-mediated fibrogenic signaling to ALK1-mediated chondrogenic signaling in joint cells represents the critical transition from a non-reparative to a reparative cell phenotype. Data from cell and in vivo studies illustrates the mechanism by which ablation of ADAMTS5 activity allows the transition to reparative chondrogenesis. Multiple large gene expression studies of normal and osteoarthritis (OA) human cartilages (CAs) also support an important role for TGFβ1-mediated pro-fibrogenic activities during disease progression.
  
  
  CONCLUSIONS
  We conclude that progressive articular CA damage in post-injury OA results primarily from biomechanical, cell biologic and mediator changes that promote a fibroblastic phenotype in joint cells. Since ADAMTS5 and TGFβ1 appear to control this process, agents which interfere with their activities may not only enhance endogenous CA repair in vivo, but also improve the properties of tissue-engineered CA for implantation.
authors.affiliation: Department of Internal Medicine (Rheumatology), Rush University Medical Center, Chicago, IL, USA.
authors.forename: A
authors.initials: A
authors.lastname: Plaas
authors.forename: J
authors.initials: J
authors.lastname: Velasco
authors.forename: D J
authors.initials: DJ
authors.lastname: Gorski
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: A
authors.initials: A
authors.lastname: Cole
authors.forename: K
authors.initials: K
authors.lastname: Christopherson
authors.forename: J D
authors.initials: JD
authors.lastname: Sandy
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000071116:ADAMTS5 Protein; D029404:Activin Receptors / Q000378:metabolism; D000818:Animals; D002358:Cartilage, Articular / Q000293:injuries / Q000503:physiopathology*; D019902:Chondrocytes / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D010003:Osteoarthritis / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D051381:Rats; D013582:Synovial Fluid / Q000737:chemistry; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014947:Wounds and Injuries / Q000150:complications
chemical_list: D053773:Transforming Growth Factor beta1; D029404:Activin Receptors; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C498489:Adamts5 protein, mouse