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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: The low-density lipoprotein receptor-related protein (Lrp)-5 functions as a Wnt coreceptor.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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Regression of hyaloid vessels is defective in Lrp5āˆ’/āˆ’ mice. (A) Schematic indicating the location of the temporary ocular capillary networks including the hyaloid vessels (vasa hyaloidia propria), the TVL and PM. (B) Quantification of the number of hyaloid vessels during a developmental timecourse for wild-type (red line) and Lrp5āˆ’/āˆ’ mice (green line). (C) Quantification of the apoptotic index (apoptotic capillary segments per total capillary segments) within the hyaloid vessels during a developmental time course for wild-type (red line) and Lrp5āˆ’/āˆ’ mice (green line). Whole-mount preparations of hyaloid vessels for wild-type (Dā€“F) and Lrp5āˆ’/āˆ’ mice (Gā€“I). Hyaloid vessel preparations are shown as pairs of brightfield and fluorescence images. Brightfield images are shown in the upper panel of each pair. In the lower panel, DAPI labeling of nuclei is shown in blue and apoptotic cell detection in red. The normal process of regression in wild-type hyaloid vessels is apparent (D to F) as is the lack of regression and a lower number of apoptotic capillary segments in Lrp5āˆ’/āˆ’ hyaloid vessels (G to I). Dā€“I are at 50Ɨ magnification.
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fig8: Regression of hyaloid vessels is defective in Lrp5āˆ’/āˆ’ mice. (A) Schematic indicating the location of the temporary ocular capillary networks including the hyaloid vessels (vasa hyaloidia propria), the TVL and PM. (B) Quantification of the number of hyaloid vessels during a developmental timecourse for wild-type (red line) and Lrp5āˆ’/āˆ’ mice (green line). (C) Quantification of the apoptotic index (apoptotic capillary segments per total capillary segments) within the hyaloid vessels during a developmental time course for wild-type (red line) and Lrp5āˆ’/āˆ’ mice (green line). Whole-mount preparations of hyaloid vessels for wild-type (Dā€“F) and Lrp5āˆ’/āˆ’ mice (Gā€“I). Hyaloid vessel preparations are shown as pairs of brightfield and fluorescence images. Brightfield images are shown in the upper panel of each pair. In the lower panel, DAPI labeling of nuclei is shown in blue and apoptotic cell detection in red. The normal process of regression in wild-type hyaloid vessels is apparent (D to F) as is the lack of regression and a lower number of apoptotic capillary segments in Lrp5āˆ’/āˆ’ hyaloid vessels (G to I). Dā€“I are at 50Ɨ magnification.

Mentions: Postnatal development of the rodent eye involves the regression of three related vascular networks called the pupillary membrane (PM), tunica vasculosa lentis (TVL), and the hyaloid vessels (Fig. 8 A). In wild-type mice, regression of these networks is normally complete by P12 for the PM and by P16 for the TVL and hyaloid vessels (Ito and Yoshioka, 1999). Histological analysis of eyes at 6 mo of age revealed the presence of hyaloid vessels in 70% (28/40) of Lrp5āˆ’/āˆ’ mice and in none of the wild-type controls. To define the onset of this phenotype, we performed a series of dissections of the capillary networks in order to compare their rates of regression. Although both the PM and TVL showed mild delays in regression (unpublished data), this response was dramatic in the hyaloid vessels; quantification of the number of capillary segments over a P3ā€“P8 time course (Fig. 8 B) indicated that loss of segments was much slower in Lrp5āˆ’/āˆ’ mice. The presence of equal numbers of capillary segments in wild-type and Lrp5āˆ’/āˆ’ mice at P3 indicated that the persistence was not a trivial consequence of early vessel overgrowth in Lrp5āˆ’/āˆ’ mice. The persistence of the hyaloid vessels is readily visualized when comparing histological preparations from wild-type (Fig. 8, Dā€“F) and Lrp5āˆ’/āˆ’ mice (Fig. 8, Gā€“I) over the P3ā€“P8 time course. Higher magnifications of hyaloid vessel preparations (Fig. 2, Gā€“L) indicate that the number of macrophages associated with wild-type and Lrp5āˆ’/āˆ’ hyaloid vessels is not different. No delay in hyaloid vessel regression was detected in Lrp+/āˆ’ mice (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)

Regression of hyaloid vessels is defective in Lrp5āˆ’/āˆ’ mice. (A) Schematic indicating the location of the temporary ocular capillary networks including the hyaloid vessels (vasa hyaloidia propria), the TVL and PM. (B) Quantification of the number of hyaloid vessels during a developmental timecourse for wild-type (red line) and Lrp5āˆ’/āˆ’ mice (green line). (C) Quantification of the apoptotic index (apoptotic capillary segments per total capillary segments) within the hyaloid vessels during a developmental time course for wild-type (red line) and Lrp5āˆ’/āˆ’ mice (green line). Whole-mount preparations of hyaloid vessels for wild-type (Dā€“F) and Lrp5āˆ’/āˆ’ mice (Gā€“I). Hyaloid vessel preparations are shown as pairs of brightfield and fluorescence images. Brightfield images are shown in the upper panel of each pair. In the lower panel, DAPI labeling of nuclei is shown in blue and apoptotic cell detection in red. The normal process of regression in wild-type hyaloid vessels is apparent (D to F) as is the lack of regression and a lower number of apoptotic capillary segments in Lrp5āˆ’/āˆ’ hyaloid vessels (G to I). Dā€“I are at 50Ɨ magnification.
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Related In: Results  -  Collection

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fig8: Regression of hyaloid vessels is defective in Lrp5āˆ’/āˆ’ mice. (A) Schematic indicating the location of the temporary ocular capillary networks including the hyaloid vessels (vasa hyaloidia propria), the TVL and PM. (B) Quantification of the number of hyaloid vessels during a developmental timecourse for wild-type (red line) and Lrp5āˆ’/āˆ’ mice (green line). (C) Quantification of the apoptotic index (apoptotic capillary segments per total capillary segments) within the hyaloid vessels during a developmental time course for wild-type (red line) and Lrp5āˆ’/āˆ’ mice (green line). Whole-mount preparations of hyaloid vessels for wild-type (Dā€“F) and Lrp5āˆ’/āˆ’ mice (Gā€“I). Hyaloid vessel preparations are shown as pairs of brightfield and fluorescence images. Brightfield images are shown in the upper panel of each pair. In the lower panel, DAPI labeling of nuclei is shown in blue and apoptotic cell detection in red. The normal process of regression in wild-type hyaloid vessels is apparent (D to F) as is the lack of regression and a lower number of apoptotic capillary segments in Lrp5āˆ’/āˆ’ hyaloid vessels (G to I). Dā€“I are at 50Ɨ magnification.
Mentions: Postnatal development of the rodent eye involves the regression of three related vascular networks called the pupillary membrane (PM), tunica vasculosa lentis (TVL), and the hyaloid vessels (Fig. 8 A). In wild-type mice, regression of these networks is normally complete by P12 for the PM and by P16 for the TVL and hyaloid vessels (Ito and Yoshioka, 1999). Histological analysis of eyes at 6 mo of age revealed the presence of hyaloid vessels in 70% (28/40) of Lrp5āˆ’/āˆ’ mice and in none of the wild-type controls. To define the onset of this phenotype, we performed a series of dissections of the capillary networks in order to compare their rates of regression. Although both the PM and TVL showed mild delays in regression (unpublished data), this response was dramatic in the hyaloid vessels; quantification of the number of capillary segments over a P3ā€“P8 time course (Fig. 8 B) indicated that loss of segments was much slower in Lrp5āˆ’/āˆ’ mice. The presence of equal numbers of capillary segments in wild-type and Lrp5āˆ’/āˆ’ mice at P3 indicated that the persistence was not a trivial consequence of early vessel overgrowth in Lrp5āˆ’/āˆ’ mice. The persistence of the hyaloid vessels is readily visualized when comparing histological preparations from wild-type (Fig. 8, Dā€“F) and Lrp5āˆ’/āˆ’ mice (Fig. 8, Gā€“I) over the P3ā€“P8 time course. Higher magnifications of hyaloid vessel preparations (Fig. 2, Gā€“L) indicate that the number of macrophages associated with wild-type and Lrp5āˆ’/āˆ’ hyaloid vessels is not different. No delay in hyaloid vessel regression was detected in Lrp+/āˆ’ mice (unpublished data).

Bottom Line: The low-density lipoprotein receptor-related protein (Lrp)-5 functions as a Wnt coreceptor.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