Transplantation of transduced chondrocytes protects articular cartilage from interleukin 1-induced extracellular matrix degradation.
Gene therapy used in the context of delivering a therapeutic gene(s) to chondrocytes offers a new approach for treating chondrocyte-mediated cartilage degradation associated with various human arthropathies including osteoarthritis. In this study, gene delivery to human osteoarthritis chondrocytes in monolayer culture was demonstrated using two adenoviral vectors (Ad.CMVlacZ and Ad.RSVntlacZ) carrying the Escherichia coli beta-galactosidase marker gene, and a third vector (Ad.RSV hIL-1ra) containing the cDNA for human interleukin-1 receptor antagonist. At an moi of 10(3) plaque-forming units/chondrocyte, > 90% of the infected cells stained positive for E. coli beta-galactosidase activity, indicating a high efficiency of transduction. Genetically modified chondrocytes were then transplanted onto the articular surface of osteoarthritic cartilage organ cultures with and without the underlying subchondral bone. Both in situ staining of the cartilage organ cultures for E. coli beta-galactosidase activity and examination by scanning electron microscopy indicated that the transplanted chondrocytes adhered and integrated into the articular surface and continued to express transgenic protein. Chondrocytes transduced with Ad.RSV hIL-1ra and seeded onto the surface of osteoarthritic cartilage secreted high levels of biologically active IL-1 receptor antagonist. The Ad.RSV hIL-1ra-treated cartilage samples were resistant to IL1-induced proteoglycan degradation over 10 d of sustained organ culture. These data demonstrate that transplantation of transduced chondrocytes onto the articular surface protects cartilage from IL-1-induced extracellular matrix degradation.
Baragi
V M
VM
Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
Renkiewicz
R R
RR
Jordan
H
H
Bonadio
J
J
Hartman
J W
JW
Roessler
B J
BJ
D000256:Adenoviridae / Q000235:genetics; D000368:Aged; D002358:Cartilage, Articular / Q000473:pathology*; D017690:Cell Transplantation; D005109:Extracellular Matrix / Q000187:drug effects / Q000473:pathology*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008875:Middle Aged; D009924:Organ Culture Techniques; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D012795:Sialoglycoproteins / Q000235:genetics* / Q000494:pharmacology* / Q000627:therapeutic use
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D011994:Recombinant Proteins; D012795:Sialoglycoproteins