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Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor.

Kato M, Patel MS, Levasseur R, Lobov I, Chang BH, Glass DA, Hartmann C, Li L, Hwang TH, Brayton CF, Lang RA, Karsenty G, Chan L - J. Cell Biol. (2002)

Bottom Line: 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.Moreover, these features recapitulate human osteoporosis-pseudoglioma syndrome, caused by LRP5 inactivation.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biology and Medicine, Baylor College of Medicine, Houston, TX 77030, USA.

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.

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Targeted disruption of Lrp5. (A) Structure of the Lrp5 protein and location of targeted disruption of Lrp5 (vertical arrow). (B) Northern blot analysis showing a broad pattern of Lrp5 expression. Gapdh was used as a control for RNA integrity. (C) Northern blot analysis showing no Lrp5 transcript in Lrp52/2 animals using a 39 probe (left) and the presence of a truncated transcript when using a 59 probe (right).
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fig1: Targeted disruption of Lrp5. (A) Structure of the Lrp5 protein and location of targeted disruption of Lrp5 (vertical arrow). (B) Northern blot analysis showing a broad pattern of Lrp5 expression. Gapdh was used as a control for RNA integrity. (C) Northern blot analysis showing no Lrp5 transcript in Lrp52/2 animals using a 39 probe (left) and the presence of a truncated transcript when using a 59 probe (right).

Mentions: Lrp5 encodes a 1,614-amino acid transmembrane protein with an extracellular domain containing EGF-like and LDLR domains, a small transmembrane domain, and an intracellular domain (Fig. 1 A). Lrp5 is very broadly expressed (Fig. 1 B). To inactivate Lrp5 in mice, we generated an allele that disrupts the extracellular domain, resulting in a truncated polypeptide due to the insertion of an IRES-LacZ-Neomycin cassette at amino acid 373 (Fig. S1, A and B). A very similar mutation is found in human patients and results in the same phenotypic consequences as those observed with a complete deletion of the gene (Gong et al., 2001).


Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor.

Kato M, Patel MS, Levasseur R, Lobov I, Chang BH, Glass DA, Hartmann C, Li L, Hwang TH, Brayton CF, Lang RA, Karsenty G, Chan L - J. Cell Biol. (2002)

Targeted disruption of Lrp5. (A) Structure of the Lrp5 protein and location of targeted disruption of Lrp5 (vertical arrow). (B) Northern blot analysis showing a broad pattern of Lrp5 expression. Gapdh was used as a control for RNA integrity. (C) Northern blot analysis showing no Lrp5 transcript in Lrp52/2 animals using a 39 probe (left) and the presence of a truncated transcript when using a 59 probe (right).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199263&req=5

fig1: Targeted disruption of Lrp5. (A) Structure of the Lrp5 protein and location of targeted disruption of Lrp5 (vertical arrow). (B) Northern blot analysis showing a broad pattern of Lrp5 expression. Gapdh was used as a control for RNA integrity. (C) Northern blot analysis showing no Lrp5 transcript in Lrp52/2 animals using a 39 probe (left) and the presence of a truncated transcript when using a 59 probe (right).
Mentions: Lrp5 encodes a 1,614-amino acid transmembrane protein with an extracellular domain containing EGF-like and LDLR domains, a small transmembrane domain, and an intracellular domain (Fig. 1 A). Lrp5 is very broadly expressed (Fig. 1 B). To inactivate Lrp5 in mice, we generated an allele that disrupts the extracellular domain, resulting in a truncated polypeptide due to the insertion of an IRES-LacZ-Neomycin cassette at amino acid 373 (Fig. S1, A and B). A very similar mutation is found in human patients and results in the same phenotypic consequences as those observed with a complete deletion of the gene (Gong et al., 2001).

Bottom Line: 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.Moreover, these features recapitulate human osteoporosis-pseudoglioma syndrome, caused by LRP5 inactivation.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biology and Medicine, Baylor College of Medicine, Houston, TX 77030, USA.

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.

Show MeSH
Related in: MedlinePlus