Compositions and methods of modulating endochondral ossification and bone formation

Patent metadata

Field	Value
Publication number	US-11097034-B2
Application number	US-201716468547-A
Country	US
Kind code	B2
Filing date	Dec 11, 2017
Priority date	Dec 11, 2016
Publication date	Aug 24, 2021
Grant date	Aug 24, 2021

Abstract

A method of modulating transdifferentiation of chondrocytes to osteoblast includes administering to the chondrocytes an agent that modulates GP130 receptor signaling and expression of at least one of Sox2, Oct4, or Nanog of the chondrocytes.

First claim

Having described the invention, we claim:

1. A method of inducing bone formation, bone repair, and/or bone regeneration in a subject in need thereof, the method comprising:
administering to chondrocytes of the subject a therapeutically effective amount of:
(i) leukemia inhibitory factor (LIF) to induce transdifferentiation of the chondrocytes to osteoblasts; and optionally at least one of
(ii) Wnt Surrogate (WntS); or
(iii) carbachol, wherein the chondrocytes are in the subject at a site of bone fracture, bone disease, bone injury, or bone abnormality, and wherein the LIF, and optionally at least one of the WntS and carbachol is injected directly into the site of bone fracture, bone disease, bone injury, or bone abnormality.

2. The method of claim 1 , administering to chondrocytes of the subject
(i) LIF;
(ii) WntS; and
(iii) carbachol.

3. The method of claim 1 , wherein the LIF induces a pluripotency like state that primes the chondrocytes for differentiation to osteoblasts.

4. The method of claim 1 , wherein the WntS promotes differentiation of the chondrocytes to osteoblasts.

5. The method of claim 1 , wherein the chondrocytes comprise hypertrophic chondrocytes.

6. The method of claim 5 , wherein the LIF, the WntS, and/or carbochol is injected directly into soft cartilage callus at a bone fracture site.

7. The method of claim 5 , wherein the bone injury comprises at least one of a delayed union fracture, nonunion fracture, hypertrophic nonunion, or growth plate disorder.

8. The method of claim 1 , wherein the chondrocytes are provided in at least one of a cartilage graft or tissue engineered construct.

9. The method of claim 1 , wherein LIF, the WntS, and/or carbachol is provided in a delivery vehicle that provides controlled release of LIF, WntS, and/or carbachol to the chondrocytes, the controlled release comprising at least one of a delayed, sustained, gradient, temporal, patterned, or spatial release.

10. A method of treating at least one of a delayed union bone fracture, nonunion bone fracture, or hypertrophic bone nonunion in a subject in need thereof, the method comprising:
administering to soft cartilage callus at a site of the bone fracture or bone nonunion a therapeutically effective amount of:
(i) leukemia inhibitory factor (LIF) to induce transdifferentiation of chondrocytes to osteoblasts; and at least one of
(ii) Wnt Surrogate (WntS); or
(iii) carbachol, wherein the LIF, and at least one of (WntS), and carbachol are injected directly into soft cartilage callus at the site.

11. The method of claim 10 , administering to the subject:
(i) LIF;
(ii) WntS; and
(iii) carbachol.

12. The method of claim 10 , wherein LIF induces a pluripotency like state of the chondrocytes of the soft callus that primes the chondrocytes for differentiation to osteoblasts.

13. The method of claim 10 , wherein the WntS promotes differentiation of chondrocytes to osteoblasts.

14. The method of claim 10 , further comprising administering to the subject at least one of a cartilage graft or tissue engineered construct.

15. The method of claim 10 wherein LIF, WntS, and/or carbachol is provided in a delivery vehicle that provides controlled release of the LIF, the WntS, and/or carbachol to the soft cartilage callus the controlled release comprising at least one of a delayed, sustained, gradient, temporal, patterned, or spatial release.

Assignees

• Case Western Reserve Univeristy
• Univ Of California San Francisco
• Univ Case Western Reserve
• Univ California

Inventors

• Alsberg Eben
• Jeon Oju
• Marcucio Ralph
• Bahney Chelsea
• Hu Diane
• Knox Sarah

Classifications

• A61L27/3821

  Bone-forming cells, e.g. osteoblasts, osteocytes, osteoprogenitor cells · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61L27/3847 Primary

  Bones · CPC title

• A61K38/204

  IL-6 · CPC title

• A61K31/5578

  having a pentalene ring system, e.g. carbacyclin, iloprost · CPC title