Peptides having osteoblast growth-promoting activity and use thereof

Abstract

The present invention provides a novel peptide having bone formation-promoting effect and chondrocyte growth-promoting effect, in particular, a peptide having osteoblast growth-promoting activity, having 100 amino acid residues or less comprising an amino acid sequence selected from (a) (SEQ ID NO: 1) Val-Asn-Pro-Glu-Ser-Glu-Glu-Glu-Asp-Glu-Ser-Ser- Pro-Tyr-Glu, (b) an amino acid sequence derived from the amino acid sequence (a) by conservative substitution or deletion of 1 to 3 amino acids, and (c) an amino acid sequence consisting of at least four contiguous amino acids of the amino acid sequence (a) or (b), or a derivative thereof or a salt thereof.

1 - 32 . (canceled) 
     
     
         33 . A method for preventing, treating or alleviating a cartilage disorder or a joint disease, the method comprising administering, to a mammal in need thereof, an effective amount of the peptide having 100 amino acid residues or less comprising an amino acid sequence selected from 
       
         
           
                 
               
                   (a) 
                 
                   (SEQ ID NO: 1) 
                 
                   Val-Asn-Pro-Glu-Ser-Glu-Glu-Glu-Asp-Glu-Ser-Ser- 
                 
                   Pro-Tyr-Glu, 
                 
             
                
                
                
                
               
            
           
         
         (b) an amino acid sequence derived from the amino acid sequence (a) by conservative substitution or deletion of 1 to 3 amino acids, and 
         (c) an amino acid sequence consisting of at least four contiguous amino acids of the amino acid sequence (a) or (b), or 
         a derivative thereof or a salt thereof. 
       
     
     
         34 . The method according to  claim 33 , wherein the peptide or a derivative thereof or a salt thereof can have at least one phosphorylated serine. 
     
     
         35 . The method according to  claim 33 , wherein the peptide or a derivative thereof or a salt thereof is a fragment of lipovitellin-1. 
     
     
         36 . The method according to  claim 33 , wherein the peptide or a derivative thereof or a salt thereof has one or more activity which is selected from the group consisting of promotion of chondrocyte growth, promotion of hyaluronic acid production, induction of chondrogenic cell differentiation, promotion of mesenchymal stem cell growth, induction of mesenchymal stem cell differentiation and increase of the serum level of insulin-like growth factor (IGF-1) in a mammal and promotion of osteoblast growth, inhibition of bone resorption. 
     
     
         37 . The method according to  claim 33 , wherein the peptide is administered orally. 
     
     
         38 . The method according to  claim 33 , wherein the peptide is included in a medicament, a food or drink, a supplement, a food additive or a cosmetic product. 
     
     
         39 . The method according to  claim 33 , wherein the peptide or a derivative thereof or a salt thereof, which consists of an amino acid sequence selected from 
       
         
           
                 
               
                   (i) 
                 
                   (SEQ ID NO: 1) 
                 
                   Val-Asn-Pro-Glu-Ser-Glu-Glu-Glu-Asp-Glu-Ser-Ser-Pro- 
                 
                   Tyr-Glu, 
                 
                     
                 
                   (ii) 
                 
                   (SEQ ID NO: 2) 
                 
                   Val-Asn-Pro-Glu-Ser-Glu-Glu-Glu, 
                 
                     
                 
                   (iii) 
                 
                   (SEQ ID NO: 3) 
                 
                   Val-Asn-Pro-Glu-Ser-Glu-Glu, 
                 
                     
                 
                   (iv) 
                 
                   (SEQ ID NO: 4) 
                 
                   Pro-Glu-Ser-Glu-Glu, 
                 
                     
                 
                   (v) 
                 
                   (SEQ ID NO: 5) 
                 
                   Asp-Glu-Ser-Ser-Pro-Tyr-Glu, 
                 
                   and 
                 
                     
                 
                   (vi) 
                 
                   (SEQ ID NO: 6) 
                 
                   Glu-Asp-Glu-Ser-Ser-Pro-Tyr-Glu. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         40 . The method according to  claim 39 , wherein the peptide or a salt thereof has one or more activity which is selected from the group consisting of promotion of chondrocyte growth, promotion of hyaluronic acid production, induction of chondrogenic cell differentiation, promotion of mesenchymal stem cell growth, induction of mesenchymal stem cell differentiation and increase of the serum level of insulin-like growth factor (IGF-1) in a mammal, promotion of osteoblast growth and inhibition of bone resorption. 
     
     
         41 . A method for promoting bone formation, the method comprising administering, to a mammal in need thereof, an effective amount of the peptide having 100 amino acid residues or less comprising an amino acid sequence selected from
 (a) Val-Asn-Pro-Glu-Ser-Glu-Glu-Glu-Asp-Glu-Ser-Ser-Pro-Tyr-Glu (SEQ ID NO:1),   (b) an amino acid sequence derived from the amino acid sequence (a) by conservative substitution or deletion of 1 to 3 amino acids, and   (c) an amino acid sequence consisting of at least four contiguous amino acids of the amino acid sequence (a) or (b), or   a derivative thereof or a salt thereof,   wherein the peptide can have at least one phosphorylated serine.   
     
     
         42 . The method according to  claim 41 , wherein the peptide or a derivative thereof or a salt thereof has one or more activity which is selected from the group consisting of promotion of chondrocyte growth, promotion of hyaluronic acid production, induction of chondrogenic cell differentiation, promotion of mesenchymal stem cell growth, induction of mesenchymal stem cell differentiation and increase of the serum level of insulin-like growth factor (IGF-1) in a mammal, promotion of osteoblast growth, and inhibition of bone resorption. 
     
     
         43 . The method according to  claim 41 , wherein the peptide is administered orally. 
     
     
         44 . The method according to  claim 41 , wherein the peptide is included in a medicament, a food or drink, a supplement, a food additive or a cosmetic product. 
     
     
         45 . The method according to  claim 41 , wherein said peptide consists of an amino acid sequence selected from the group consisting of 
       
         
           
                 
               
                   (i) 
                 
                   (SEQ ID NO: 1) 
                 
                   Val-Asn-Pro-Glu-Ser-Glu-Glu-Glu-Asp-Glu-Ser-Ser-Pro- 
                 
                   Tyr-Glu, 
                 
                     
                 
                   (ii) 
                 
                   (SEQ ID NO: 2) 
                 
                   Val-Asn-Pro-Glu-Ser-Glu-Glu-Glu, 
                 
                     
                 
                   (iii) 
                 
                   (SEQ ID NO: 3) 
                 
                   Val-Asn-Pro-Glu-Ser-Glu-Glu, 
                 
                     
                 
                   (iv) 
                 
                   (SEQ ID NO: 4) 
                 
                   Pro-Glu-Ser-Glu-Glu, 
                 
                     
                 
                   (v) 
                 
                   (SEQ ID NO: 5) 
                 
                   Asp-Glu-Ser-Ser-Pro-Tyr-Glu, 
                 
                   and 
                 
                     
                 
                   (vi) 
                 
                   (SEQ ID NO: 6) 
                 
                   Glu-Asp-Glu-Ser-Ser-Pro-Tyr-Glu, 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       wherein the peptide does not have phosphorylated serine. 
     
     
         46 . The method according to  claim 45 , wherein the peptide or a salt thereof has one or more activity which is selected from the group consisting of promotion of chondrocyte growth, promotion of hyaluronic acid production, induction of chondrogenic cell differentiation, promotion of mesenchymal stem cell growth, induction of mesenchymal stem cell differentiation and increase of the serum level of insulin-like growth factor (IGF-1) in a mammal, promotion of osteoblast growth, inhibition of bone resorption. 
     
     
         47 . A peptide or a derivative thereof or a salt thereof, which consists of an amino acid sequence selected from 
       
         
           
                 
               
                   (i) 
                 
                   (SEQ ID NO: 1) 
                 
                   Val-Asn-Pro-Glu-Ser-Glu-Glu-Glu-Asp-Glu-Ser-Ser-Pro- 
                 
                   Tyr-Glu, 
                 
                     
                 
                   (ii) 
                 
                   (SEQ ID NO: 2) 
                 
                   Val-Asn-Pro-Glu-Ser-Glu-Glu-Glu, 
                 
                     
                 
                   (iii) 
                 
                   (SEQ ID NO: 3) 
                 
                   Val-Asn-Pro-Glu-Ser-Glu-Glu, 
                 
                     
                 
                   (iv) 
                 
                   (SEQ ID NO: 4) 
                 
                   Pro-Glu-Ser-Glu-Glu, 
                 
                     
                 
                   (v) 
                 
                   (SEQ ID NO: 5) 
                 
                   Asp-Glu-Ser-Ser-Pro-Tyr-Glu, 
                 
                   and 
                 
                     
                 
                   (vi) 
                 
                   (SEQ ID NO: 6) 
                 
                   Glu-Asp-Glu-Ser-Ser-Pro-Tyr-Glu, 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       wherein the peptide can have at least one phosphorylated serine. 
     
     
         48 . The peptide or a derivative thereof or a salt thereof according to  claim 47 , wherein the peptide or a derivative thereof or a salt thereof has one or more activity which is selected from the group consisting of promotion of chondrocyte growth, promotion of hyaluronic acid production, induction of chondrogenic cell differentiation, promotion of mesenchymal stem cell growth, induction of mesenchymal stem cell differentiation and increase of the serum level of insulin-like growth factor (IGF-1) in a mammal, promotion of bone formation, promotion of osteoblast growth, and inhibition of bone resorption.