Methods of treatment involving p21/CIP1

Abstract

The onset ratios and pathological conditions of collagen-induced arthritis and adjuvant arthritis in model mice and rats, respectively, were successfully ameliorated by topically expressing the cyclin-dependent kinase inhibitors p16 INK4a and p21 Cip1 p in articular tissues using adenoviral vectors. In the synovial cells of CDKI-transduced mice, expression of inflammatory cytokines was inhibited. Described are the use of the p21 Cip1 protein for inhibiting abnormal proliferation of synovial tissues, inflammation in synovial tissues and/or expression of inflammatory cytokines in synovial tissues; the p21 Cip1 gene; compounds promoting the activity or expression of the p21 Cip1 protein; and pharmaceutical compositions containing these molecules. Also provided are method of screening for compounds participating in the abnormal proliferation of synovial tissues, inflammation in synovial tissues and/or the expression of inflammatory cytokines in synovial tissues targeting the p21 Cip1 protein. Rheumatoid arthritis and other disorders associated with inflammation of the synovial tissue can be prevented or treated by promoting expression or function of p21 Cip1 protein.

1 . A method of treating aberrant growth or inflammation of synovial tissue or expression of inflammatory cytokines insynovial tissue, the method comprising:
 (a) identifying a subject in need of treatment for aberrant growth or inflammation of synovial tissue or expression of inflammatory cytokines in synovial tissue; and   (b) increasing the amount or function of a p21 Cip1  protein in a joint of the subject by administering to the subject a compound selected from the group consisting of:
 (i) a p21 Cip1  protein or a vector encoding a p21 Cip1  protein, 
 (ii) a compound that promotes the activity of p21 Cip1  protein, 
 (iii) a compound that inhibits the degradation of p21 Cip1  protein, and 
 (iv) a compound that promotes the expression of an endogenous p21 Cip1  gene. 
   
     
     
         2 . The method of  claim 2 , wherein the method comprises administering to the subject a p21 Cip1  protein or a vector encoding a p21 Cip1  protein. 
     
     
         3 . The method of  claim 3 , wherein the method comprises administering to the subject a vector encoding a p21 Cip1  protein. 
     
     
         4 . The method of  claim 3 , wherein the vector is an adenovirus vector. 
     
     
         5 . The method of  claim 1 , wherein the method comprises administering to the subject a compound selected from the group consisting of:
 (a) a compound that promotes the activity of p21 Cip1  protein,   (b) a compound that inhibits the degradation of p21 Cip1  protein, and   (c) a compound that promotes the expression of an endogenous p21 Cip1  gene.   
     
     
         6 . The method of  claim 1 , wherein the subject has rheumatoid arthritis. 
     
     
         7 . The method of  claim 2 , wherein the subject has rheumatoid arthritis. 
     
     
         8 . The method of  claim 3 , wherein the subject has rheumatoid arthritis. 
     
     
         9 . The method of  claim 4 , wherein the subject has rheumatoid arthritis. 
     
     
         10 . The method of  claim 5 , wherein the subject has rheumatoid arthritis. 
     
     
         11 . A method of screening for a compound that inhibits aberrant growth or inflammation of synovial tissue or expression of inflammatory cytokines in synovial tissue, the method comprising the steps of:
 (a) contacting a p21 Cip1  protein with a test compound,   (b) detecting an activity of the p21 Cip1  protein in the presence of the test compound, and   (c) selecting a test compound that causes an inhibition in the activity of the p21 Cip1  protein compared to the activity of the p21 Cip1  protein in the absence of the test compound.   
     
     
         12 . A method of screening for a compound that inhibits aberrant growth or inflammation of synovial tissue or expression of inflammatory cytokines in synovial tissue, the method comprising the steps of:
 (a) contacting a p21 Cip1  protein with a test compound,   (b) detecting the amount of the p21 Cip1  protein in the presence of the test compound, and   (c) selecting a compound that increases the amount of the p21 Cip1  protein compared to the amount of the p21 Cip1  protein in the absence of the test compound.   
     
     
         13 . A method of screening for a compound that inhibits aberrant growth or inflammation of synovial tissue or expression of inflammatory cytokines in synovial tissue, comprising the steps of:
 (a) providing a cell comprising an endogenous p21 Cip1  gene,   (b) contacting the cell with a test compound,   (c) detecting the amount of a transcriptional product of the endogenous p21 Cip1  gene in the presence of the test compound, and   (d) selecting a compound that increases the amount of the transcriptional product of the p21 Cip1  gene, compared to the amount of the p21 Cip1  transcriptional product in the absence of the test compound.   
     
     
         14 . A method of screening for a compound that inhibits aberrant growth or inflammation of synovial tissue or expression of inflammatory cytokines in synovial tissue, the method comprising the steps of:
 (a) contacting a cell with a test compound, wherein the cell comprises a vector in which a regulatory domain which is normally associated with an endogenous p21 Cip1  gene is operably linked to a reporter gene,   (b) detecting an activity of the reporter gene in the presence of the test compound, and   (c) selecting a compound that increases the activity of the reporter gene compared to the activity of the reporter gene in the absence of the test compound.   
     
     
         15 . The method of  claim 11 , further comprising the step of testing the selected compound in an animal model of rheumatoid arthritis. 
     
     
         16 . The method of  claim 12 , further comprising the step of testing the selected compound in an animal model of rheumatoid arthritis. 
     
     
         17 . The method of  claim 13 , further comprising the step of testing the selected compound in an animal model of rheumatoid arthritis. 
     
     
         18 . The method of  claim 14 , further comprising the step of testing the selected compound in an animal model of rheumatoid arthritis. 
     
     
         19 . A method of treating rheumatoid arthritis in a subject, the method comprising identifying a subject in need of treatment for rheumatoid arthritis, and administering a p21 Cip1  protein or a vector encoding a p21 Cip1  protein into an arthritic joint of the subject. 
     
     
         20 . The method of  claim 19 , wherein the vector is an adenovirus vector.