Use of osteoprotegerin (OPG) to increase human pancreatic beta cell survival and proliferation
View Patent ↗It is disclosed herein that osteoprotegerin increases human beta cell proliferation and survival. Methods are provided for increasing beta cell proliferation, but contacting a beta cell with an effective amount of osteoprotegrin, a functional fragment, variant or fusion protein thereof. Methods are also provided for treating a human subject with diabetes, comprising administering to the subject a therapeutically effective amount of osteoprotegerin, functional variant or fusion protein thereof.
1. A method of increasing proliferation of a human beta cell, comprising
contacting the human beta cell with an effective amount of
(a) a wild type human osteoprotegerin, an osetoprotegerin polypeptide comprising the amino acid sequence set forth as SEQ ID NO: 1, or an osetoprotegerin polyeptide comprising the amino acids 22-401 of the amino acid sequence set forth as SEQ ID NO: 1, or
(b) a fusion protein thereof that binds receptor activator of nuclear factor kappa-B ligand (RANKL),
thereby increasing proliferation of the human beta cell.
2. The method of claim 1 , wherein the human beta cell is in vivo.
3. The method of claim 1 , wherein the human beta cell is in vitro.
4. The method of claim 1 , further comprising measuring proliferation of the human beta cell.
5. The method of claim 1 , comprising contacting the beta cell with an effective amount of the osetoprotegerin polypeptide comprising the amino acid sequence set forth as SEQ ID NO: 1 or the osteoprotegerin polypeptide comprising amino acids 22-401 of SEQ ID NO: 1.
6. The method of claim 1 , wherein the human beta cell is a human beta cell from an adult subject.
7. The method of claim 6 , further comprising measuring proliferation of the human beta cell.
8. The method of claim 7 , wherein measuring proliferation of the human beta cell comprises measuring incorporation of bromodeoxyuridine or Ki-67 into genomic DNA of the beta cell and/or progeny of the human beta cell.
9. The method of claim 7 , wherein measuring proliferation of the human beta cell comprises measuring incorporation of a membrane permeable cell proliferation dye into the human beta cell and/or progeny of the human beta cell.
10. The method of claim 1 , comprising contacting the human beta cell with the fusion protein, wherein the fusion protein comprises an immunoglobulin Fc.
11. The method of claim 1 , comprising contacting the human beta cell with the wild-type human oteoprotegerin.
12. The method of claim 1 , comprising contacting the human beta cell with the fusion protein.
13. A method of increasing survival of a human beta cell, comprising
contacting the human beta cell with an effective amount of
a) a wild-type human osteoprotegerin polypeptide, an osteoprotegerin polypeptide comprising the amino acid sequence set forth as SEQ ID NO: 1 or an osteoprotegerin polypeptide comprising amino acids 22-401 of the amino sequence set forth as SEQ ID NO: 1, or
b) a fusion protein thereof that-binds receptor activator of nuclear factor kappa-B ligand (RANKL),
thereby increasing survival of the human beta cell.
14. The method of claim 13 , wherein the human beta cell is in vivo.
15. The method of claim 13 , wherein the human beta cell is in vitro.
16. The method of claim 13 , further comprising measuring survival of the human beta cell.
17. The method of claim 13 , comprising contacting the beta cell with the effective amount of the wild-type human osteoprotegerin or the osteoprotegerin polypeptide comprising the amino acid sequence set forth as SEQ ID NO: 1.
18. The method of claim 13 , wherein the human beta cell is a human beta cell of an adult subject.
19. The method of claim 13 , comprising contacting the human beta cell with the fusion protein, wherein the fusion protein comprises an immunoglobulin Fc.
20. The method of claim 13 , comprising contacting the human beta cell with the oteoprotegerin polypeptide comprising amino acids 22 to 401 of the amino acid sequence set forth as SEQ ID NO: 1.
21. The method of claim 13 , comprising contacting the human beta cell with the fusion protein.