RRC ID 12698
Author Nonomura Y, Kohsaka H, Nasu K, Terada Y, Ikeda M, Miyasaka N.
Title Suppression of arthritis by forced expression of cyclin-dependent kinase inhibitor p21(Cip1) gene into the joints.
Journal Int Immunol
Abstract Rheumatoid synovial fibroblasts (RSF) express cyclin-dependent kinase (CDK) inhibitors p16(INK4a) and p21(Cip1) when they are growth-inhibited in vitro. The induction of p16(INK4a) is characteristic of RSF and intra-articular p16(INK4a) gene therapy has been shown to suppress adjuvant arthritis (AA) of rats. The other inducible CDK inhibitor, p21(Cip1), has multiple functions depending on the cell type. They include inhibition of CDK as well as promotion of active CDK complex formation and induction of apoptosis. This study is to discern the biological effects of p21(Cip1) gene transfer into RSF and its therapeutic effects on AA. A recombinant adenovirus containing a human p21(Cip1) gene and control adenoviruses were prepared. RSF infected with these viruses were examined for their cell growth. Apoptotic cell death was evaluated by nuclear staining and DNA fragmentation analysis. In vivo gene therapy of rat AA was carried out by intra-articular injection of the viruses. Severity of the arthritis was clinically scored. The treated joints were examined histologically and proliferating cell nuclear antigens (PCNA) were detected immunohistochemically. The adenoviral p21(Cip1) gene transfer inhibited growth of RSF without inducing apoptosis. p21(Cip1) gene therapy suppressed AA clinically and histologically. The effects were comparable to p16(INK4a) gene therapy. PCNA expression was reduced in the p21(Cip1)-treated joints. The adenoviral gene transfer of p21(Cip1) ameliorated rat AA. The effect was attributable to inhibition of proliferation. Because p21(Cip1) is induced more easily by many chemicals than p16(INK4a), it also appears to be a feasible target in developing anti-rheumatic drugs.
Volume 13(6)
Pages 723-31
Published 2001-6-1
DOI 10.1093/intimm/13.6.723
PMID 11369699
MeSH Adenoviridae / genetics Animals Apoptosis / genetics Arthritis, Experimental / enzymology Arthritis, Experimental / prevention & control* Cells, Cultured Cyclin-Dependent Kinase Inhibitor p21 Cyclin-Dependent Kinases / antagonists & inhibitors* Cyclin-Dependent Kinases / genetics* Cyclins / administration & dosage* Cyclins / biosynthesis Cyclins / genetics* Enzyme Inhibitors / administration & dosage* Fibroblasts / enzymology Fibroblasts / metabolism Gene Transfer Techniques Genetic Therapy Genetic Vectors / administration & dosage Hindlimb Humans Injections, Intra-Articular Joints / enzymology* Male Rats Rats, Inbred Lew Synovial Membrane / metabolism Synovial Membrane / pathology
IF 3.519
Times Cited 32
DNA material Ax1w1 (RDB 1746)