Abstract
Both the Wnt/beta-catenin and Ihh signaling pathways play essential roles in crucial aspects of endochondral ossification: osteoblast differentiation, chondrocyte proliferation and hypertrophy. To understand the genetic interaction between these two signaling pathways, we have inactivated the beta-catenin gene and upregulated Ihh signaling simultaneously in the same cells during endochondral skeletal development using beta-catenin and patched 1 floxed alleles. We uncovered previously unexpected roles of Ihh signaling in synovial joint formation and the essential function of Wnt/beta-catenin signaling in regulating chondrocyte survival. More importantly, we found that Wnt and Ihh signaling interact with each other in distinct ways to control osteoblast differentiation, chondrocyte proliferation, hypertrophy, survival and synovial joint formation in the developing endochondral bone. Beta-catenin is required downstream of Ihh signaling and osterix expression for osteoblast differentiation. But in chondrocyte survival, beta-catenin is required upstream of Ihh signaling to inhibit chondrocyte apoptosis. In addition, Ihh signaling can inhibit chondrocyte hypertrophy and synovial joint formation independently of beta-catenin. However, there is a strong synergistic interaction between Wnt/beta-catenin and Ihh signaling in regulating synovial joint formation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Apoptosis / genetics
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Apoptosis / physiology
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Bone and Bones / cytology
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Bone and Bones / embryology
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Bone and Bones / metabolism
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Cartilage / cytology
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Cartilage / embryology
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Cartilage / metabolism
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Cell Cycle / genetics
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Cell Cycle / physiology
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Cell Differentiation / genetics
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Cell Differentiation / physiology
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Cell Proliferation
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Cell Survival / genetics
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Cell Survival / physiology
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Chondrocytes / cytology
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Chondrocytes / enzymology
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Chondrocytes / metabolism*
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Gene Expression Regulation, Developmental
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Hedgehog Proteins
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Immunohistochemistry
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In Situ Hybridization
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In Situ Nick-End Labeling / methods
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Intracellular Signaling Peptides and Proteins / metabolism*
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Joints / cytology
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Joints / embryology
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Joints / metabolism*
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Mice
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Osteoblasts / cytology
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Osteoblasts / metabolism
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Osteogenesis / genetics
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Osteogenesis / physiology
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Patched Receptors
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Patched-1 Receptor
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism
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Receptors, Cell Surface / physiology
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Signal Transduction / genetics
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Signal Transduction / physiology*
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Wnt Proteins / chemistry
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Wnt Proteins / metabolism*
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beta Catenin / genetics
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beta Catenin / metabolism*
Substances
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Hedgehog Proteins
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Intracellular Signaling Peptides and Proteins
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PTCH1 protein, human
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Patched Receptors
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Patched-1 Receptor
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Ptch1 protein, mouse
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Receptors, Cell Surface
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Wnt Proteins
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beta Catenin
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ihh protein, mouse