TGF beta-induced cartilage repair is maintained but fibrosis is blocked in the presence of Smad7.
Cartilage damage in osteoarthritis (OA) is considered an imbalance between catabolic and anabolic factors, favoring the catabolic side. We assessed whether adenoviral overexpression of transforming growth factor-beta (TGFbeta) enhanced cartilage repair and whether TGFbeta-induced fibrosis was blocked by local expression of the intracellular TGFbeta inhibitor Smad7. We inflicted cartilage damage by injection of interleukin-1 (IL-1) into murine knee joints. After 2 days, we injected an adenovirus encoding TGFbeta. On day 4, we measured proteoglycan (PG) synthesis and content. To examine whether we could block TGFbeta-induced fibrosis and stimulate cartilage repair simultaneously, we injected Ad-TGFbeta and Ad-Smad7. This was performed both after IL-1-induced damage and in a model of primary OA. In addition to PG in cartilage, synovial fibrosis was measured by determining the synovial width and the number of procollagen I-expressing cells. Adenoviral overexpression of TGFbeta restored the IL-1-induced reduction in PG content and increased PG synthesis. TGFbeta-induced an elevation in PG content in cartilage of the OA model. TGFbeta-induced synovial fibrosis was strongly diminished by simultaneous synovial overexpression of Smad7 in the synovial lining. Of great interest, overexpression of Smad7 did not reduce the repair-stimulating effect of TGFbeta on cartilage. Adenoviral overexpression of TGFbeta stimulated repair of IL-1- and OA-damaged cartilage. TGFbeta-induced synovial fibrosis was blocked by locally inhibiting TGFbeta signaling in the synovial lining by simultaneously transfecting it with an adenovirus overexpressing Smad7.
Experimental Rheumatology and Advanced Therapeutics, St, Radboud University Medical Centre Nijmegen, Geert Grooteplein 26-28, 6525 GA Nijmegen, The Netherlands. e.blaneydavidson@reuma.umcn.nl
Esmeralda N
EN
Blaney Davidson
Elly L
EL
Vitters
Wim B
WB
van den Berg
Peter M
PM
van der Kraan
D000818:Animals; D002356:Cartilage / Q000187:drug effects / Q000473:pathology*; D004195:Disease Models, Animal; D005355:Fibrosis / Q000517:prevention & control*; D005822:Genetic Vectors; D007375:Interleukin-1 / Q000633:toxicity; D007719:Knee Joint / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010003:Osteoarthritis / Q000473:pathology / Q000517:prevention & control; D011994:Recombinant Proteins / Q000494:pharmacology; D051906:Smad7 Protein / Q000502:physiology*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000494:pharmacology*; D014945:Wound Healing / Q000187:drug effects*
D007375:Interleukin-1; D011994:Recombinant Proteins; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D016212:Transforming Growth Factor beta