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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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Related in: MedlinePlus

Low bone mass in Lrp5−/− mice. (A) Radiograph of the whole body of 2 mo-old wild-type and Lrp5−/− mice showing decreased lucency of the entire Lrp5−/− skeleton. (B) Histological analysis of vertebrae from 2-mo-old wild-type and Lrp5−/− mice showing low bone mass in the mutant mice. (C) Histological analysis of vertebrae from 2-wk-old wild-type and Lrp5−/− mice showing a decreased number of trabeculae in the primary spongiosa of Lrp5−/− mice. (D) Lrp5−/− mice have a lower bone mass throughout life. Green triangle indicates a significantly lower bone mass in Lrp5+/− mice. Asterisks indicate a statistically significant difference between two groups of mice (P < 0.05). Error bars represent SD.
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fig3: Low bone mass in Lrp5−/− mice. (A) Radiograph of the whole body of 2 mo-old wild-type and Lrp5−/− mice showing decreased lucency of the entire Lrp5−/− skeleton. (B) Histological analysis of vertebrae from 2-mo-old wild-type and Lrp5−/− mice showing low bone mass in the mutant mice. (C) Histological analysis of vertebrae from 2-wk-old wild-type and Lrp5−/− mice showing a decreased number of trabeculae in the primary spongiosa of Lrp5−/− mice. (D) Lrp5−/− mice have a lower bone mass throughout life. Green triangle indicates a significantly lower bone mass in Lrp5+/− mice. Asterisks indicate a statistically significant difference between two groups of mice (P < 0.05). Error bars represent SD.

Mentions: A small number of mutant animals were limping while walking, suggesting the existence of a skeleton-related abnormality. Radiographic analysis of one of these mutant mice at 2 mo of age revealed the presence of a fracture in the tibia betraying the existence of a low bone mass phenotype (Fig. S2) that was present in all Lrp5−/− mice at that age (Fig. 3 A; unpublished data).


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)

Low bone mass in Lrp5−/− mice. (A) Radiograph of the whole body of 2 mo-old wild-type and Lrp5−/− mice showing decreased lucency of the entire Lrp5−/− skeleton. (B) Histological analysis of vertebrae from 2-mo-old wild-type and Lrp5−/− mice showing low bone mass in the mutant mice. (C) Histological analysis of vertebrae from 2-wk-old wild-type and Lrp5−/− mice showing a decreased number of trabeculae in the primary spongiosa of Lrp5−/− mice. (D) Lrp5−/− mice have a lower bone mass throughout life. Green triangle indicates a significantly lower bone mass in Lrp5+/− mice. Asterisks indicate a statistically significant difference between two groups of mice (P < 0.05). Error bars represent SD.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Low bone mass in Lrp5−/− mice. (A) Radiograph of the whole body of 2 mo-old wild-type and Lrp5−/− mice showing decreased lucency of the entire Lrp5−/− skeleton. (B) Histological analysis of vertebrae from 2-mo-old wild-type and Lrp5−/− mice showing low bone mass in the mutant mice. (C) Histological analysis of vertebrae from 2-wk-old wild-type and Lrp5−/− mice showing a decreased number of trabeculae in the primary spongiosa of Lrp5−/− mice. (D) Lrp5−/− mice have a lower bone mass throughout life. Green triangle indicates a significantly lower bone mass in Lrp5+/− mice. Asterisks indicate a statistically significant difference between two groups of mice (P < 0.05). Error bars represent SD.
Mentions: A small number of mutant animals were limping while walking, suggesting the existence of a skeleton-related abnormality. Radiographic analysis of one of these mutant mice at 2 mo of age revealed the presence of a fracture in the tibia betraying the existence of a low bone mass phenotype (Fig. S2) that was present in all Lrp5−/− mice at that age (Fig. 3 A; unpublished data).

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