Composition and use of rar antagonists for promoting chondrogenesis

Abstract

The invention provides compositions comprising a RAR antagonist for promoting chondrogenesis and to methods employing such compositions for treating cartilage and associated bone abnormalities resulting from injury or disease and for ex vivo tissue engineering.

1 - 29 . (canceled) 
   
   
       30 . A composition comprising:
 (a) an RAR antagonist;   (b) a pharmaceutically acceptable carrier; and   (c) a chondrogenic stimulator,   wherein said composition induces chondrogenesis leading to cartilage formation or chondrogenesis leading to cartilage formation that further mediates formation of new bone tissue in a vertebrate.   
   
   
       31 . The composition according to  claim 30 , wherein said chondrogenic stimulator is a protein selected from the group consisting of a bone morphogenetic protein (BMP), an osteogenic protein (OP), a cytokine and combinations thereof. 
   
   
       32 . The composition according to  claim 31 , wherein said BMP is selected from the group consisting of BMP-2, BMP-4 and BMP-5. 
   
   
       33 . The composition according to  claim 31 , wherein said osteogenic protein is OP-1. 
   
   
       34 . The composition according to  claim 30 , wherein the RAR antagonist is present in an amount for stimulating chondrogenesis. 
   
   
       35 . The composition according to  claim 30 , wherein said composition is provided as a solution, suspension, gel, matrix, cream, film, paste, capsule, pill or tablet, or is encapsulated within liposomes. 
   
   
       36 . The composition according to  claim 30 , wherein said composition is for intra-articular injection. 
   
   
       37 . The composition according to  claim 30 , wherein said composition is provided within a biodegradable implantable matrix. 
   
   
       38 . The composition according to  claim 30 , wherein said composition is for the treatment of arthritis, abnormal cartilage formation and/or cartilage defects. 
   
   
       39 . The composition according to  claim 30 , wherein said RAR antagonist antagonizes one or more of RARα, RARβ and RARγ. 
   
   
       40 . A device for implantation in a vertebrate, comprising:
 (a) an implantable biocompatible carrier; and   (b) a RAR antagonist dispersed within or on said carrier.   
   
   
       41 . The device according to  claim 40 , wherein said carrier comprises demineralized bone, protein-extracted bone, particulate bone, allogenic bone, xenogenic bone or combinations thereof. 
   
   
       42 . The device according to  claim 40 , wherein said carrier is selected from the group consisting of semi-permeable polymer matrices, hydroxyapatite, collagen, tricalcium phosphate and copolymers of glycolic, lactic and butyric acid. 
   
   
       43 . The device according to  claim 40 , wherein said device comprises a biodegradable sponge. 
   
   
       44 . The device according to  claim 40 , wherein said device is a prosthetic for repairing an orthopaedic defect, injury or anomaly in a vertebrate. 
   
   
       45 . The device according to  claim 44 , wherein said device has a surface region implantable adjacent or within a target tissue and said RAR antagonist is disposed on said surface region in an amount sufficient to promote enhanced chondrogenesis and associated bone tissue growth into said surface. 
   
   
       46 . The device according to of  claim 40 , wherein said RAR antagonist is provided within a composition further comprising a pharmaceutically acceptable carrier and a chondrogenic stimulator. 
   
   
       47 . The device according to  claim 46 , wherein said chondrogenic stimulator is a protein selected from the group consisting of a bone morphogenetic protein (BMP), an osteogenic protein (OP), a cytokine and combinations thereof. 
   
   
       48 . The device according to  claim 40 , wherein said RAR antagonist antagonizes one or more of RARα, RARβ and RARγ. 
   
   
       49 . A method for producing a chondrocyte from a chondroprogenitor mesenchymal cell, comprising contacting said chondroprogenitor mesenchymal cell with an RAR antagonist or a RAR antagonist composition according to claim  1  in vitro. 
   
   
       50 . The method according to  claim 49 , wherein said chondrocytes are implanted into a cartilage defect in vivo to produce cartilage at said site. 
   
   
       51 . The method according to  claim 49 , wherein said RAR antagonist antagonizes one or more of RARα, RARβ and RARγ. 
   
   
       52 - 56 . (canceled) 
   
   
       57 . A method for stimulating chondroblast differentiation, comprising delivering an effective amount of a RAR antagonist to inhibit RAR activity. 
   
   
       58 . The method of  claim 57 , wherein said RAR antagonist amount decreases transcriptional activation of the RA receptor.