Abstract
Mutations in the Wnt co-receptor LRP5 alter bone mass in humans, but the mechanisms responsible for Wnts actions in bone are unclear. To investigate the role of the classical Wnt signaling pathway in osteogenesis, we generated mice lacking the beta-catenin or adenomatous polyposis coli (Apc) genes in osteoblasts. Loss of beta-catenin produced severe osteopenia with striking increases in osteoclasts, whereas constitutive activation of beta-catenin in the conditional Apc mutants resulted in dramatically increased bone deposition and a disappearance of osteoclasts. In vitro, osteoblasts lacking the beta-catenin gene exhibited impaired maturation and mineralization with elevated expression of the osteoclast differentiation factor, receptor activated by nuclear factor-kappaB ligand (RANKL), and diminished expression of the RANKL decoy receptor, osteoprotegerin. By contrast, Apc-deficient osteoblasts matured normally but demonstrated decreased expression of RANKL and increased osteoprotegerin. These findings suggest that Wnt/beta-catenin signaling in osteoblasts coordinates postnatal bone acquisition by controlling the differentiation and activity of both osteoblasts and osteoclasts.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenomatous Polyposis Coli Protein / genetics
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Adenomatous Polyposis Coli Protein / physiology
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Animals
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Animals, Newborn
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Bone Diseases, Metabolic / genetics
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Bone Diseases, Metabolic / metabolism
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Bone and Bones / metabolism*
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Carrier Proteins / metabolism
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Cell Differentiation
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Cytoskeletal Proteins / metabolism
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Cytoskeletal Proteins / physiology*
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Enzyme-Linked Immunosorbent Assay
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Female
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Femur / metabolism
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Gene Expression Regulation
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Genes, APC
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Genotype
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Glycoproteins / metabolism
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Green Fluorescent Proteins / metabolism
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Immunohistochemistry
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / physiology*
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Male
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Membrane Glycoproteins / metabolism
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Mice
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Mice, Transgenic
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Mutation
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Osteoblasts / metabolism
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Osteoclasts / metabolism
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Osteoprotegerin
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Cytoplasmic and Nuclear / metabolism
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Receptors, Tumor Necrosis Factor / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Sex Factors
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Signal Transduction
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Time Factors
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Tomography, X-Ray Computed
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Trans-Activators / metabolism
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Trans-Activators / physiology*
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Wnt Proteins
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beta Catenin
Substances
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Adenomatous Polyposis Coli Protein
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CTNNB1 protein, mouse
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Carrier Proteins
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Cytoskeletal Proteins
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Glycoproteins
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Intercellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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Osteoprotegerin
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Cytoplasmic and Nuclear
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Receptors, Tumor Necrosis Factor
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Tnfrsf11a protein, mouse
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Tnfrsf11b protein, mouse
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Tnfsf11 protein, mouse
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Trans-Activators
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Wnt Proteins
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beta Catenin
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Green Fluorescent Proteins