Open AccessRemodelling of human osteoarthritic cartilage by FGF‐2, alone or combined with Sox9 via rAAV gene transfer
Author(s) -
Cucchiarini Magali,
Terwilliger Ernest F.,
Kohn Dieter,
Madry Henning
Publication year - 2009
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2008.00474.x
Subject(s) - sox9 , gene transfer , cartilage , osteoarthritis , articular cartilage , fibroblast growth factor , gene , genetic enhancement , medicine , pathology , biology , gene expression , anatomy , genetics , alternative medicine , receptor
Compensating for the loss of extracellular cartilage matrix, as well as counteracting the alterations of the chondrocyte phenotype in osteoarthritis are of key importance to develop effective therapeutic strategies against this disorder. In the present study, we analysed the benefits of applying a potent gene combination to remodel human osteoarthritic (OA) cartilage. We employed the promising recombinant adeno‐associated virus (rAAV) vector to deliver the mitogenic fibroblast growth factor 2 (FGF‐2) factor, alone or simultaneously with the transcription factor Sox9 as a key activator of matrix synthesis, to human normal and OA articular chondrocytes. We evaluated the effects of single (FGF‐2) or combined (FGF‐2/ SOX9 ) transgene expression upon the regenerative activities of chondrocytes in three‐dimensional cultures in vitro and in cartilage explants in situ . Single overexpression of FGF‐2 enhanced the survival and proliferation of both normal and OA chondrocytes, without stimulating the matrix synthetic processes in the increased pools of cells. The mitogenic properties of FGF‐2 were maintained when SOX9 was co‐overexpressed and concomitant with an increase in the production of proteoglycans and type‐II collagen, suggesting that the transcription factor was capable of counterbalancing the effects of FGF‐2 on matrix accumulation. Also important, expression of type‐X collagen, a marker of hypertrophy strongly decreased following treatment by the candidate vectors. Most remarkably, the levels of activities achieved in co‐treated human OA cartilage were similar to or higher than those observed in normal cartilage. The present findings show that combined expression of candidate factors in OA cartilage can re‐establish key features of normal cartilage and prevent the pathological shift of metabolic homeostasis. These data provide further motivation to develop coupled gene transfer approaches via rAAV for the treatment of human OA.