Compositions and methods of modulating endochondral ossification and bone formation

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.

1 . A method of modulating transdifferentiation of chondrocytes to osteoblasts, the method comprising:
 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, wherein the agent comprises at least one of leukemia inhibitory factor (LIF) or a LIF receptor agonist.   
     
     
         2 - 4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein the chondrocytes comprise hypertrophic chondrocytes. 
     
     
         6 . The method of  claim 5 , wherein the chondrocytes are in a subject at a site of bone fracture, bone disease, bone injury, or bone abnormality. 
     
     
         7 . The method of  claim 6 , wherein the agent is administered locally to soft cartilage callus at the site. 
     
     
         8 . The method of  claim 1 , wherein the agent is injected directly into soft cartilage callus at a bone fracture site. 
     
     
         9 . The method of  claim 6 , wherein the bone injury comprises at least one of a delayed union fracture, nonunion fracture, hypertrophic nonunion, or growth plate disorder. 
     
     
         10 . The method of  claim 1 , wherein the chondrocytes are provided in at least one of a cartilage graft or tissue engineered construct. 
     
     
         11 . The method of  claim 1 , further comprising administering to the activated chondrocytes an agent that activates canonical Wnt signaling in the chondrocytes. 
     
     
         12 . The method of  claim 11 , wherein the agent promotes differentiation of the activated chondrocytes to osteoblasts. 
     
     
         13 . The method of  claim 11 , wherein the agent comprises at least one of a Wnt ligand or agonist or an inhibitor of a negative regulator of Wnt signaling. 
     
     
         14 . The method of  claim 13 , wherein the Wnt ligand or agonist comprises at least one of a frizzled receptor agonist, Wnt1, Wnt2, Wnt2b, Wnt3, Wnt3a, Wnt4, Wnt5a, Wnt5b, Wnt6, Wnt7a, Wnt7b, Wnt8a, Wnt8b, Wnt9a, Wnt9b, Wnt10a, Wnt10b, Wnt11, Wnt16, Norrin ligand, or R-spondin2. 
     
     
         15 . The method of  claim 13 , wherein the inhibitor of a negative regulator of Wnt signaling includes at least one of a glycogen synthase kinase 3 (GSK-3) inhibitor, a PKA inhibitor, a PKC inhibitor, a MEK1/2 inhibitor, a MAPK inhibitor, a JNK inhibitor, a DKK inhibitor, or a sclerostin inhibitor. 
     
     
         16 . The method of  claim 11 , wherein the agent that activates canonical Wnt signaling is injected directly into soft cartilage callus at a bone fracture site. 
     
     
         17 . The method of  claim 11 , further comprising administering to the chondrocytes at least one of a cholinergic agonist, muscarinic agonist, or nicotinic agonist to promote bone regeneration. 
     
     
         18 . The method of  claim 17 , wherein the cholinergic agonist comprises at least one of acetylcholine or an acetylcholine analogue. 
     
     
         19 . The method of  claim 18 , wherein the acetylcholine analogue includes carbachol. 
     
     
         20 . The method of  claim 17 , wherein the agent, the canonical Wnt signaling activator, the cholinergic agonist, the muscarinic agonist, or the nicotinic agonist is provided in a delivery vehicle that provides controlled release of the agent, the canonical Wnt signaling activator, the cholinergic agonist, the muscarinic agonist, and/or the nicotinic agonist to the chondrocytes, the controlled release comprising at least one of a delayed, sustained, gradient, temporal, patterned, or spatial release. 
     
     
         21 - 73 . (canceled)