Abstract
The low-density lipoprotein receptor-related protein (Lrp)-5 functions as a Wnt coreceptor. Here we show that mice with a targeted disruption of Lrp5 develop a low bone mass phenotype. In vivo and in vitro analyses indicate that this phenotype becomes evident postnatally, and demonstrate that it is secondary to decreased osteoblast proliferation and function in a Cbfa1-independent manner. Lrp5 is expressed in osteoblasts and is required for optimal Wnt signaling in osteoblasts. In addition, Lrp5-deficient mice display persistent embryonic eye vascularization due to a failure of macrophage-induced endothelial cell apoptosis. These results implicate Wnt proteins in the postnatal control of vascular regression and bone formation, two functions affected in many diseases. Moreover, these features recapitulate human osteoporosis-pseudoglioma syndrome, caused by LRP5 inactivation.
Publication types
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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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Animals
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Apoptosis
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Bone Development
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Bone Diseases, Metabolic / metabolism
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Bone Diseases, Metabolic / pathology*
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Bone and Bones / metabolism
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Bone and Bones / pathology
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Calcium / blood
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Calcium / urine
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Cell Division
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Core Binding Factor Alpha 1 Subunit
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Eye / cytology
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Eye / pathology
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Eye Abnormalities / metabolism*
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Eye Abnormalities / pathology
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Gene Expression Regulation, Developmental
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Immunohistochemistry
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In Situ Nick-End Labeling
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LDL-Receptor Related Proteins
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Low Density Lipoprotein Receptor-Related Protein-5
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Macrophages / immunology
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Macrophages / pathology
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Mice
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Mice, Knockout
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Mutagenesis, Site-Directed
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Neoplasm Proteins*
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Organ Size
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Osteoblasts / metabolism*
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Osteoblasts / pathology*
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Phenotype
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Receptors, LDL / deficiency*
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Receptors, LDL / genetics
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Receptors, LDL / immunology
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Receptors, LDL / metabolism
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Signal Transduction
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Transcription Factors / physiology*
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Wnt Proteins
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Zebrafish Proteins*
Substances
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Core Binding Factor Alpha 1 Subunit
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LDL-Receptor Related Proteins
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LRP5 protein, human
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Low Density Lipoprotein Receptor-Related Protein-5
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Lrp5 protein, mouse
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Neoplasm Proteins
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Proto-Oncogene Proteins
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Receptors, LDL
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Transcription Factors
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Wnt Proteins
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Zebrafish Proteins
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Calcium