Methods for accelerating bone, cartilage, and connective tissue growth

Abstract

The present invention provides improved methods, kits, and compositions for enhancing bone, cartilage and cartilage repair, bone and prosthesis implantation, and attachment and fixation of cartilage and cartilage to bone or other tissues, and chondrocyte proliferation comprising the administration of an effective amount of angiotensinogen, angiotensin I (AI), AI analogues, AI fragments and analogues thereof, angiotensin II (AII), AII analogues, AII fragments or analogues thereof or AII AT 2 type 2 receptor agonists.

1 . A method for enhancing bone repair in a mammal, comprising the administration of an amount effective for enhancing bone repair in the mammal of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 1 -R 8  in the sequence of general formula I  
         R 1 —R 2 —R 3 —R 4 —R 5 —R 6 —R 7 —R 8    in which R 1  and R 2  together form a group of formula      X—R A —R B —,    wherein X is H or a one to three peptide group, or is absent,    R A  is suitably selected from H, Asp, Glu, Asn, Acpc (1-aminocyclopentane carboxylic acid), Ala, Me 2 Gly, Pro, Bet, Glu(NH 2 ), Gly, Asp(NH 2 ) and Suc,    R B  is suitably selected from Arg, Lys, Ala, Om, Citron, Ser(Ac), Sar, D-Arg and D-Lys;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ala, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr, excluding sequences including R 4  as a terminal Tyr group, or is absent.    
     
     
         2 . The method of  claim 1  wherein the active agent is selected from the group consisting of angiotensinogen, SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO: 32, SEQ ID NO:33, SEQ ID NO: 34; SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, and SEQ ID NO:45.  
     
     
         3 . The method of  claim 1  further comprising administration of an amount effective for enhancing bone repair in the mammal of at least one compound selected from bone morphogenic protein-2, bone morphogenic protein-4, bone morphogenic protein-6, bone morphogenic protein-7, transforming growth factor-beta, insulin-like growth factor, and parathyroid hormone.  
     
     
         4 . An improved method for bone and prosthesis implantation in a mammal, comprising the administration of an amount effective for enhancing bone and prosthesis implantation in the mammal of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 1 -R 8  in the sequence of general formula I  
         R 1 —R 2 —R 3 —R 4 —R 5 —R 6 —R 7 —R 8    in which R 1  and R 2  together form a group of formula      X—R A —R B —,    wherein X is H or a one to three peptide group, or is absent,    R A  is suitably selected from H, Asp, Glu, Asn, Acpc (1-aminocyclopentane carboxylic acid), Ala, Me 2 Gly, Pro, Bet, Glu(NH 2 ), Gly, Asp(NH 2 ) and Suc,    R B  is suitably selected from Arg, Lys, Ala, Om, Citron, Ser(Ac), Sar, D-Arg and D-Lys;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ala, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr, excluding sequences including R 4  as a terminal Tyr group, or is absent.    
     
     
         5 . The method of  claim 4  wherein the active agent is selected from the group consisting of angiotensinogen, SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO: 32, SEQ ID NO:33, SEQ ID NO: 34; SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, and SEQ ID NO:45.  
     
     
         6 - 26 . (canceled)  
     
     
         27 . A method for enhancing bone repair in a mammal, comprising the administration of an amount effective for enhancing bone repair in the mammal of at least one active agent of the formula  
         Asp-Arg-R1-R2-Ile-His-Pro-R2, wherein  R1 is selected from the group consisting of Ile, Pro, Ala, Val, Leu, and norLeu;    R2 is selected from Tyr and Tyr(PO 3 ) 2 ; and    R3 is Phe, or is absent.    
     
     
         28 . The method of  claim 27  wherein the active agent is selected from the group consisting of SEQ ID NO:1, SEQ ID NO:4, SEQ ID NO:24, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO: 33, SEQ ID NO:41, and SEQ ID NO: 45.  
     
     
         29 . The method of  claim 27  further comprising the administration of an amount effective for enhancing bone repair in the mammal of at least one compound selected from bone morphogenic protein-2, bone morphogenic protein-4, bone morphogenic protein-6, bone morphogenic protein-7, transforming growth factor-beta, insulin-like growth factor, and parathyroid hormone.  
     
     
         30 - 48 . (canceled)