Synthetic triterpenoids and tricyclic-bis-enones for use in stimulating bone and cartilage growth
The present invention concerns methods for stimulating the growth and repair of bone and cartilage using synthetic triterpenoids and tricyclic-bis-enones. Examples of suitable triterpenoids include CDDO, CDDO-Me, CDDO-Im, and CDDO-Ethylamide. Examples of tricyclic-bis-enones include TBE-31 and TBE-34.
1. A method for stimulating a bone-forming or osteochondrogenic cell comprising:
a) providing a bone-producing or osteochondrogenic cell;
b) contacting said cell with an effective amount of a compound having the structure:
wherein Y is hydroxy, methoxy, ethyl-amino, or
a pharmaceutically acceptable salt or tautomer thereof; and
c) culturing the cell.
2. The method of claim 1 , wherein the cell is of human origin.
3. The method of claim 1 , wherein the cell is of bovine, equine, canine, feline, murine, rat or chick origin.
4. The method of claim 1 , further comprising incubating said cell with a growth factor.
5. The method of claim 4 , wherein the growth factor is TGF-β1, TGF-β2, TGF-β1.2, VEGF, insulin-like growth factor I or II, BMP2, BMP4, or BMP7.
6. The method of claim 4 , wherein the growth factor is parathyroid hormone, calcitonin, interleukin-6, or interleukin-11.
7. The method of claim 1 , further comprising purifying said cell after step (b).
8. The method of claim 1 , further comprising implanting said cell in vivo after step (b) and/or step (c).
9. The method of claim 1 , wherein bone is formed by said cell.
10. The method of claim 1 , wherein the cell is an osteoblast.
11. A method of providing bone tissue to a mammal comprising:
a) providing a bone-producing cell;
b) contacting said cell with an effective amount of a compound having the structure:
wherein Y is hydroxy, methoxy, ethyl-amino, or
a pharmaceutically acceptable salt or tautomer thereof;
c) culturing the cell to form bone; and
d) implanting said bone to said subject.
12. The method of claim 11 , wherein the bone formed in step (c) is part of a three-dimensional matrix.
13. The method of claim 12 , wherein the three-dimensional matrix is one or more of alginate gels, collagen gels, or fibrin gels.
14. The method of claim 12 , wherein the three-dimensional matrix comprises one or more of polylactic acid, polyglycolic acid or PGLA.
15. The method of claim 12 , wherein the three-dimensional matrix comprises one or more of hydroxyapatite or other apatitic compounds, devitalized animal bone, devitalized human bone, or porous ceramic structures.
16. The method of claim 11 , wherein the mammal has cancer bone disease, localized osteolysis due to cancer and to myeloma, degenerative cartilage conditions, osteoarthritis, osteoporosis, Vitamin D deficiency, Osteotitis deformans, or Von Recklinghausen's Disease.
17. The method of claim 11 , wherein the cell is of human origin.
18. The method of claim 11 , wherein the cell is of bovine, equine, canine, feline, murine, rat or chick origin.
19. A method for producing bone ex vivo comprising:
a) providing a bone-producing cell;
b) contacting said cell with an effective amount of a compound having the structure:
wherein Y is hydroxy, methoxy, ethyl-amino, or
a pharmaceutically acceptable salt or tautomer thereof; and
c) culturing the cell to form bone.
20. A method of repairing bone damage in a patient having a bone defect, bone trauma, osteoarthritis, osteoporosis, or Vitamin D deficiency, comprising administering to said patient an amount of a compound effective to repair bone damage, said compound having the structure:
wherein Y is hydroxy, methoxy, ethyl-amino, or
a pharmaceutically acceptable salt or tautomer thereof.
21. A method for stimulating a cartilage-forming cell comprising:
a) providing a cartilage-producing or osteochondrogenic cell;
b) contacting said cell with an effective amount of a compound having the structure:
or
a pharmaceutically acceptable salt or tautomer thereof; and
c) culturing the cell.
22. A method of repairing cartilage damage in a patient having cartilage disease or cartilage trauma comprising administering to said patient an amount of a compound effective to repair cartilage damage, said compound having the structure:
or a pharmaceutically acceptable salt or tautomer thereof.
23. The method of claim 22 , wherein the patient is human.
24. The method of claim 22 , wherein cartilage is formed.
25. The method of claim 20 , wherein the compound is administered to a wound.
26. The method of claim 20 , wherein the compound is administered to a bone disease site.
27. The method of claim 20 , wherein the patient has bone trauma.
28. The method of claim 20 , wherein the patient has a bone defect.
29. The method of claim 28 , wherein the bone defect is the result of a birth defect.
30. The method of claim 20 , wherein the patient is human.
31. The method of claim 20 , wherein bone is formed.
32. The method of claim 27 , wherein the bone trauma is a fracture.
33. The method of claim 28 , wherein the bone defect is the result of cancer surgery.
34. The method of claim 20 , wherein the patient has osteoarthritis.
35. The method of claim 20 , wherein the patient has osteoporosis.
36. The method of claim 20 , wherein the patient has Vitamin D deficiency.