Osteoprotegerin

Abstract

The present invention discloses a novel secreted polypeptide, termed osteoprotegerin, which is a member of the tumor necrosis factor receptor superfamily and is involved in the regulation of bone metabolism. Also disclosed are nucleic acids encoding osteoprotegerin, polypeptides, recombinant vectors and host cells for expression, antibodies which bind OPG, and pharmaceutical compositions. The polypeptides are used to treat bone diseases characterized by increased resorption such as osteoporosis.

1 - 60 . (canceled) 
     
     
         61 . A truncated OPG polypeptide encoded by a nucleic acid which hybridizes under high stringency conditions corresponding to 5×SSC, 50% formamide and 42° C. and washing at 0.5×SSC at 55° C. with the complement of the nucleic acid sequence as shown in SEQ ID NO: 124, wherein the truncated OPG polypeptide comprises at least about 164 amino acids comprising four cysteine-rich domains characteristic of the cysteine rich domains of tumor necrosis factor extracellular regions and has the activity of inhibiting bone resorption. 
     
     
         62 . The polypeptide of  claim 61  comprising cysteine residues at positions 41, 44, 54, 62, 65, 80, 83, 87, 98, 105, 107, 118, 124, 142, 145, 160, 166 and 185 as shown in SEQ ID NO: 125. 
     
     
         63 . The polypeptide of  claim 61  further comprising an Fc region of human IgG or a derivative of an Fc region of human IgG. 
     
     
         64 . The polypeptide of  claim 61  which is the product of an exogenous DNA in a transformed or transfected host cell. 
     
     
         65 . The polypeptide of  claim 61  wherein the exogenous DNA is cDNA, genomic DNA or synthetic DNA. 
     
     
         66 . The polypeptide of  claim 61  wherein the host cell is a prokaryotic or eucaryotic host cell. 
     
     
         67 . The polypeptide of  claim 66  wherein the host cell is selected from CHO, COS, 293, 3T3, CV-1 or BHK cells. 
     
     
         68 . The polypeptide of  claim 66  wherein the host cell is  Escherichia coli.    
     
     
         69 . The polypeptide of  claim 61  further comprising a water soluble polymer. 
     
     
         70 . The polypeptide of  claim 69  wherein the water soluble polymer is polyethylene glycol or dextran. 
     
     
         71 . A pharmaceutical composition comprising a therapeutically effective amount of the polypeptide of  claim 61  and one or more of a pharmaceutically acceptable carrier, adjuvant, solubilizer, stabilizer and anti-oxidant. 
     
     
         72 . An OPG multimer comprising monomers which comprise a truncated OPG polypeptide encoded by a nucleic acid which hybridizes under high stringency conditions corresponding to 5×SSC, 50% formamide and 42° C. and washing at 0.5×SSC at 55° C. with the complement of the nucleic acid sequence as shown in SEQ ID NO: 124, wherein the truncated OPG polypeptide comprises at least about 164 amino acids comprising four cysteine-rich domains characteristic of the cysteine rich domains of tumor necrosis factor extracellular regions and the OPG multimer has the activity of inhibiting bone resorption.