Chondroitin sulfate synthesis promoter

Abstract

The invention provides a chondroitin sulfate synthesis promoter useful for the treatment of diseases such as articular disease and discopathy. The chondroitin sulfate synthesis promoter contains, as an active ingredient, chondroitin sulfate glucuronyltransferase protein and/or chondroitin sulfate N-acetylgalactosaminyltransferase-1 protein, or a gene encoding the enzyme protein(s).

1 . A chondroitin sulfate synthesis promoter comprising, as an active ingredient, at least one of a gene encoding chondroitin sulfate glucuronyltransferase and a gene encoding chondroitin sulfate N-acetylgalactosaminyltransferase-1. 
     
     
         2 . A chondroitin sulfate synthesis promoter as described in  claim 1 , wherein the gene encoding chondroitin sulfate glucuronyltransferase is a nucleic acid molecule including a nucleotide sequence defined by SEQ ID NO: 1. 
     
     
         3 . A chondroitin sulfate synthesis promoter as described in  claim 1 , wherein the gene encoding chondroitin sulfate glucuronyltransferase is a nucleic acid molecule which can be hybridized with a complement of a nucleic acid of SEQ ID NO: 1 under stringent conditions. 
     
     
         4 . A chondroitin sulfate synthesis promoter as described in  claim 1 , wherein the gene encoding chondroitin sulfate glucuronyltransferase is a nucleic acid molecule including a nucleotide sequence identical to that defined by SEQ ID NO: 1, except that one or more nucleotide(s) have been substituted, deleted, inserted, or transposed, wherein the nucleic acid molecule encodes a protein having activity of transferring glucuronate from a glucuronate donor to a non-reducing end N-acetylgalactosamine residue present in the chondroitin skeleton. 
     
     
         5 . A chondroitin sulfate synthesis promoter as described in  claim 1 , wherein the gene encoding chondroitin sulfate glucuronyltransferase is a nucleic acid molecule including a nucleotide sequence encoding an amino acid sequence defined by SEQ ID NO: 2. 
     
     
         6 . A chondroitin sulfate synthesis promoter as described in  claim 1 , wherein the gene encoding chondroitin sulfate N-acetylgalactosaminyltransferase-1 is a nucleic acid molecule including a nucleotide sequence defined by SEQ ID NO: 3. 
     
     
         7 . A chondroitin sulfate synthesis promoter as described in  claim 1 , wherein the gene encoding chondroitin sulfate N-acetylgalactosaminyltransferase-1 is a nucleic acid molecule which can be hybridized with a complement of a nucleic acid of SEQ ID NO: 3 under stringent conditions. 
     
     
         8 . A chondroitin sulfate synthesis promoter as described in  claim 1 , wherein the gene encoding chondroitin sulfate N-acetylgalactosaminyltransferase-1 is a nucleic acid molecule including a nucleotide sequence identical to that defined by SEQ ID NO: 3, except that one or more nucleotide(s) have been substituted, deleted, inserted, or transposed, wherein the nucleic acid molecule encodes a protein having activity of transferring an N-acetylgalactosamine residue from an N-acetylgalactosamine donor to a non-reducing end D-glucuronate residue of an N-acetylgalactosamine acceptor substrate containing a sugar chain represented by formula;
   GlcUA-Gal-Gal-Xyl   
       (wherein GlcUA represents a D-glucuronate residue, Gal represents a D-galactose residue, Xyl represents a D-xylose residue, and “-” represents a glycosidic linkage). 
     
     
         9 . A chondroitin sulfate synthesis promoter as described in  claim 1 , wherein the gene encoding chondroitin sulfate N-acetylgalactosaminyltransferase-1 is a nucleic acid molecule including a nucleotide sequence encoding an amino acid sequence defined by SEQ ID NO: 4. 
     
     
         10 . A chondroitin sulfate synthesis promoter as described in  claim 1 , wherein at least one of a gene encoding chondroitin sulfate glucuronyltransferase and a gene encoding chondroitin sulfate N-acetylgalactosaminyltransferase-1 are incorporated into an expression vector. 
     
     
         11 . A chondroitin sulfate synthesis promoter as described in  claim 1 , wherein at least one of a gene encoding chondroitin sulfate glucuronyltransferase and a gene encoding chondroitin sulfate N-acetylgalactosaminyltransferase-1 are incorporated into a host cell. 
     
     
         12 . A chondroitin sulfate synthesis promoter comprising, as an active ingredient, at least one of a chondroitin sulfate glucuronyltransferase and a chondroitin sulfate N-acetylgalactosaminyltransferase-1. 
     
     
         13 . A chondroitin sulfate synthesis promoter as described in  claim 12 , wherein the chondroitin sulfate glucuronyltransferase is an enzyme comprising a protein which includes an amino acid sequence defined by SEQ ID NO: 2. 
     
     
         14 . A chondroitin sulfate synthesis promoter as described in  claim 12 , wherein the chondroitin sulfate glucuronyltransferase is an enzyme comprising a protein which includes an amino acid sequence identical to that defined by SEQ ID NO: 2, except that one or more amino acid residue(s) have been substituted, deleted, inserted, or transposed, wherein the protein has activity of transferring glucuronate from a glucuronate donor to a non-reducing end N-acetylgalactosamine residue present in the chondroitin skeleton. 
     
     
         15 . A chondroitin sulfate synthesis promoter as described in  claim 12 , wherein the chondroitin sulfate N-acetylgalactosaminyltransferase-1 is an enzyme comprising a protein which includes an amino acid sequence defined by SEQ ID NO: 4. 
     
     
         16 . A chondroitin sulfate synthesis promoter as described in  claim 12 , wherein the chondroitin sulfate N-acetylgalactosaminyltransferase-1 is an enzyme comprising a protein which includes an amino acid sequence identical to that defined by SEQ ID NO: 4, except that one or more amino acid residue(s)have been substituted, deleted, inserted, or transposed, wherein the protein has activity of transferring an N-acetylgalactosamine residue from an N-acetylgalactosamine donor to a non-reducing end D-glucuronate residue of an N-acetylgalactosamine acceptor substrate containing a sugar chain represented by formula;
   GlcUA-Gal-Gal-Xyl   
       (wherein GlcUA represents a D-glucuronate residue, Gal represents a D-galactose residue, Xyl represents a D-xylose residue, and “-” represents a glycosidic linkage). 
     
     
         17 . A treatment agent for at least one of an articular disease and discopathy comprising, as an active ingredient, a chondroitin sulfate synthesis promoter comprising at least one of a chondroitin sulfate glucuronyltransferase, a gene encoding chondroitin sulfate glucuronyltransferase, a chondroitin sulfate N-acetylgalactosaminyltransferase-1, and a gene encoding a chondroitin sulfate N-acetylgalactosaminyltransferase-1. 
     
     
         18 . A treatment agent for an articular disease as described in  claim 17 , which promotes synthesis of chondroitin sulfate in cartilage. 
     
     
         19 . A cartilage repairing agent which can promote synthesis of chondroitin sulfate, the agent comprising, as an active ingredient at least one of a chondroitin sulfate glucuronyltransferase, a gene encoding chondroitin sulfate glucuronyltransferase, a chondroitin sulfate N-acetylgalactosaminyltransferase-1, and a gene encoding a chondroitin sulfate N-acetylgalactosaminyltransferase-1. 
     
     
         20 . A cartilaginous tissue formation promoter comprising, as an active ingredient, at least one of a chondroitin sulfate glucuronyltransferase, a gene encoding chondroitin sulfate glucuronyltransferase, a chondroitin sulfate N-acetylgalactosaminyltransferase-1, and a gene encoding a chondroitin sulfate N-acetylgalactosaminyltransferase-1. 
     
     
         21 . A method for promoting chondroitin sulfate synthesis in a living subject wherein the living subject includes a joint, a cartilage, an intervertebral disc or a cell, the method comprising the steps of:
 providing a gene comprising at least one of a gene encoding chondroitin sulfate glucuronyltransferase and a gene encoding chondroitin sulfate N-acetylgalactosaminyltransferase-1; and   introducing the gene into the living subject.   
     
     
         22 . A method for promoting a chondroitin sulfate synthesis in a living subject as described in  claim 21 , wherein the step of introducing the gene into the living subject is performed with a gene gun or via injection. 
     
     
         23 . A method for promoting a chondroitin sulfate synthesis in a living subject wherein the living subject includes a joint, a cartilage, an intervertebral disc or a cell, the method comprising the steps of:
 providing at least one of chondroitin sulfate glucuronyltransferase and chondroitin sulfate N-acetylgalactosaminyltransferase-1; and   introducing at least one of a chondroitin sulfate glucuronyltransferase and chondroitin sulfate N-acetylgalactosaminyltransferase-1 into the living subject.   
     
     
         24 . A method for promoting a chondroitin sulfate synthesis in a living subject as described in  claim 23 , wherein the step of introducing at least one of a chondroitin sulfate glucuronyltransferase and chondroitin sulfate N-acetylgalactosaminyltransferase-1 into the living subject is performed via injection. 
     
     
         25 . A method for treating an articular disease or discopathy, the method comprising the steps of:
 applying a therapeutically effective amount of an active ingredient comprising at least one of a chondroitin sulfate glucuronyltransferase, a gene encoding chondroitin sulfate glucuronyltransferase, a chondroitin sulfate N-acetylgalactosaminyltransferase-1, and a gene encoding a chondroitin sulfate N-acetylgalactosaminyltransferase-1 with the affected joint or intervertebral disc; and   promoting a chondroitin sulfate synthesis in the affected joint or intervertebral disc.