Abstract
In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Adult
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Animals
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Animals, Outbred Strains
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Bone Density / genetics*
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Bone Morphogenetic Protein 2
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Bone Morphogenetic Proteins / pharmacology
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COS Cells
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Child
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Child, Preschool
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Chlorocebus aethiops
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Chromosomes, Human, Pair 11 / genetics
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Culture Media, Conditioned / pharmacology
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DNA, Complementary / genetics
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Dishevelled Proteins
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Eye / embryology*
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Eye Abnormalities / genetics*
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Female
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Genes, Recessive
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Heterozygote
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Humans
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LDL-Receptor Related Proteins
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Low Density Lipoprotein Receptor-Related Protein-5
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Male
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Mesoderm / cytology
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Mice
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Mice, Inbred C57BL
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Organ Culture Techniques
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Osteoblasts / metabolism*
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Osteoporosis / genetics*
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Phosphoproteins / genetics
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Phosphoproteins / physiology
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Proteins / genetics
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Proteins / physiology
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology
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Receptors, LDL / deficiency
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Receptors, LDL / genetics
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Receptors, LDL / physiology*
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Recombinant Fusion Proteins / physiology
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Recombinant Proteins
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Signal Transduction
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Skull / cytology
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Species Specificity
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Stromal Cells / cytology
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Stromal Cells / drug effects
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Syndrome
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Transfection
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Transforming Growth Factor beta*
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Wnt Proteins
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Wnt-5a Protein
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Wnt2 Protein
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Wnt3 Protein
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Wnt4 Protein
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Zebrafish Proteins*
Substances
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Adaptor Proteins, Signal Transducing
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BMP2 protein, human
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Bmp2 protein, mouse
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Bone Morphogenetic Protein 2
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Bone Morphogenetic Proteins
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Culture Media, Conditioned
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DNA, Complementary
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Dishevelled Proteins
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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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Phosphoproteins
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Proteins
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Proto-Oncogene Proteins
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Receptors, LDL
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Recombinant Fusion Proteins
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Recombinant Proteins
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Transforming Growth Factor beta
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WNT4 protein, human
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WNT5A protein, human
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Wnt Proteins
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Wnt-5a Protein
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Wnt2 Protein
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Wnt3 Protein
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Wnt4 Protein
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Wnt4 protein, mouse
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Zebrafish Proteins
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recombinant human bone morphogenetic protein-2