Polypeptides controlling phosphoric acid metabolism, calcium metabolism, calcification and vitamin d metabolism and dnas encoding the same

Abstract

A DNA, which encodes the following polypeptide (a), (b), (c) or (d): (a) a polypeptide consisting of an amino acid sequence represented by SEQ ID NO: 2 or 4, (b) a polypeptide consisting of an amino acid sequence derived from the amino acid sequence represented by SEQ ID NO: 2 or 4 by deletion, substitution or addition of one or several amino acids, and having hypophosphatemia-inducing activity, phosphate transport-suppressing activity, calcification-suppressing activity or in vivo vitamin D metabolism-regulating activity, (c) a polypeptide consisting of a partial sequence of the amino acid sequence represented by SEQ ID NO: 2, wherein the above partial sequence contains an amino acid sequence at least ranging from the 34 th to 201 st amino acids in the above amino acid sequence, or (d) a polypeptide consisting of a partial sequence of the amino acid sequence represented by SEQ ID NO: 2, wherein the above partial sequence: (i) contains an amino acid sequence ranging from at least the 34 th to 201 st amino acids in said amino acid sequence, (ii) consists of an amino acid sequence derived from the partial sequence by deletion, substitution, or addition of one or several amino acids, and (iii) has hypophosphatemia-inducing activity, phosphate transport-suppressing activity, calcification-suppressing activity or in vivo vitamin D metabolism-regulating activity.

1 . A DNA, which encodes the following polypeptide (a), (b), (c) or (d): 
 (a) a polypeptide consisting of an amino acid sequence represented by SEQ ID NO: 2 or 4,    (b) a polypeptide consisting of an amino acid sequence derived from the amino acid sequence represented by SEQ ID NO: 2 or 4 by deletion, substitution or addition of one or several amino acids, and having hypophosphatemia-inducing activity, phosphate transport-suppressing activity, calcification-suppressing activity or in vivo vitamin D metabolism-regulating activity,    (c) a polypeptide consisting of a partial sequence of the amino acid sequence represented by SEQ ID NO: 2, wherein said partial sequence contains an amino acid sequence at least ranging from the 34 th  to 201 st  amino acids in said amino acid sequence, or    (d) a polypeptide consisting of a partial sequence of the amino acid sequence represented by SEQ ID NO: 2, wherein said partial sequence: 
 (i) contains an amino acid sequence at least ranging from the 34 th  to 201 st  amino acids in said amino acid sequence,  
 (ii) consists of an amino acid sequence derived from the partial sequence by deletion, substitution or addition of one or several amino acids, and  
 (iii) has hypophosphatemia-inducing activity, phosphate transport-suppressing activity, calcification-suppressing activity or in vivo vitamin D metabolism-regulating activity.  
   
     
     
         2 . A DNA, which contains the following DNA (e) or (f): 
 (e) a DNA consisting of a nucleotide sequence ranging from the 133 rd  to 885 th  nucleotides in the nucleotide sequence represented by SEQ ID NO: 1 or a nucleotide sequence ranging from the 1 st  to 681 st  nucleotides in the nucleotide sequence represented by SEQ ID NO: 3, or    (f) a DNA hybridizing under stringent conditions to a probe prepared from a DNA consisting of the whole or a part of the nucleotide sequence represented by SEQ ID NO: 1 or 3, and encoding a polypeptide having hypophosphatemia-inducing activity, phosphate transport-suppressing activity, calcification-suppressing activity or in vivo vitamin D metabolism-regulating activity.    
     
     
         3 . A recombinant vector, which contains the DNA of  claim 1  or  2 .  
     
     
         4 . A transformant, which contains the recombinant vector of  claim 3 .  
     
     
         5 . A polypeptide, which is the following polypeptide (a), (b), (c) or (d): 
 (a) a polypeptide consisting of an amino acid sequence represented by SEQ ID NO: 2 or 4,    (b) a polypeptide consisting of an amino acid sequence derived from the amino acid sequence represented by SEQ ID NO: 2 or 4 by deletion, substitution or addition of one or several amino acids, and having hypophosphatemia-inducing activity, phosphate transport-suppressing activity, calcification-suppressing activity or in vivo vitamin D metabolism-regulating activity,    (c) a polypeptide consisting of a partial sequence of the amino acid sequence represented by SEQ ID NO: 2, wherein said partial sequence contains at least an amino acid sequence ranging from the 34 th  to 201 st  amino acids in said amino acid sequence, or    (d) a polypeptide consisting of a partial sequence of the amino acid sequence represented by SEQ ID NO: 2 wherein said partial sequence: 
 (i) contains an amino acid sequence ranging from at least the 34 th  to 201 th  amino acids in said amino acid sequence,  
 (ii) consists of an amino acid sequence derived from the partial sequence by deletion, substitution, or addition of one or several amino acids, and  
 (iii) has hypophosphatemia-inducing activity, phosphate transport-suppressing activity, calcification-suppressing activity or in vivo vitamin D metabolism-regulating activity.  
   
     
     
         6 . The polypeptide of  claim 5 , which is modified by at least one substance selected from the group consisting of polyethylene glycol, dextran, poly(N-vinyl-pyrrolidone), polypropylene glycol homopolymer, copolymer of polypropylene oxide and polyethylene oxide, polyoxyethylated polyol and polyvinyl alcohol.  
     
     
         7 . A pharmaceutical composition, which contains the polypeptide of  claim 5  or  6  as an active ingredient.  
     
     
         8 . A pharmaceutical composition, which contains the polypeptide of  claim 5  or  6  as an active ingredient and is capable of regulating in vivo calcium metabolism, phosphate metabolism, calcification or vitamin D metabolism.  
     
     
         9 . A pharmaceutical composition, which contains the polypeptide of  claim 5  or  6  as an active ingredient and is effective against at least one disease selected from the group consisting of hyperphosphatemia, hyperparathyroidism, renal osteodystrophy, ectopic calcification, osteoporosis and hypervitaminosis D.  
     
     
         10 . An antibody, which reacts with the polypeptide of  claim 5  or  6  or partial fragments thereof.  
     
     
         11 . A method for producing the antibody of  claim 10 , which comprises the step of immunizing an animal with the polypeptide of  claim 5  or  6 , or partial fragments thereof as an antigen.  
     
     
         12 . A pharmaceutical composition, which contains the antibody of  claim 10  as an active ingredient.  
     
     
         13 . A pharmaceutical composition, which contains the antibody of  claim 10  as an active ingredient, and is capable of regulating in vivo calcium metabolism, phosphate metabolism, calcification or vitamin D metabolism.  
     
     
         14 . A pharmaceutical composition, which contains the antibody of  claim 10  as an active ingredient, and is effective against bone diseases.  
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein the bone disease is at least one disease selected from the group consisting of osteoporosis, vitamin D-resistant rickets, renal osteodystrophy, dialysis-associated bone diseases, osteopathy with hypocalcification, Paget's disease and tumor-induced osteomalacia.  
     
     
         16 . A diagnostic agent, which contains the antibody of  claim 10 , and is for a disease which develops at least one abnormality of abnormal calcium metabolism, abnormal phosphate metabolism, abnormal calcification and abnormal vitamin D metabolism.  
     
     
         17 . The diagnostic agent of  claim 16 , wherein the disease is at least one disease selected from the group consisting of renal failure, renal phosphate leak, renal tubular acidosis and Fanconi's syndrome.  
     
     
         18 . A diagnostic agent for a bone disease, which contains the antibody of  claim 10 .  
     
     
         19 . The diagnostic agent of  claim 18 , wherein the bone disease is at least one disease selected from the group consisting of osteoporosis, vitamin D-resistant rickets, renal osteodystrophy, dialysis-associated bone diseases, osteopathy with hypocalcification, Paget's disease and tumor-induced osteomalacia.  
     
     
         20 . A diagnostic agent, which contains a DNA having a nucleotide sequence represented by SEQ ID NO: 11 or partial fragments thereof, and is for a disease which develops at least one abnormality of abnormal calcium metabolism, abnormal phosphate metabolism and abnormal calcification.  
     
     
         21 . The diagnostic agent of  claim 20 , wherein the partial fragment has a sequence ranging from the 498 th  to 12966 th  nucleotides of the nucleotide sequence represented by SEQ ID NO: 11.  
     
     
         22 . The diagnostic agent of  claim 20  or  21 , wherein the disease is autosomal dominant hypophosphatemic rickets/osteomalacia.