Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor.
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.
Kato
Masaki
M
Department of Molecular and Cellular Biology and Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Patel
Millan S
MS
Levasseur
Regis
R
Lobov
Ivan
I
Chang
Benny H-J
BH
Glass
Donald A
DA
Hartmann
Christine
C
Li
Lan
L
Hwang
Tae-Ho
TH
Brayton
Cory F
CF
Lang
Richard A
RA
Karsenty
Gerard
G
Chan
Lawrence
L
D000818:Animals; D017209:Apoptosis; D001846:Bone Development; D001851:Bone Diseases, Metabolic / Q000378:metabolism / Q000473:pathology*; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000097:blood / Q000652:urine; D002455:Cell Division; D050659:Core Binding Factor Alpha 1 Subunit; D005123:Eye / Q000166:cytology / Q000473:pathology; D005124:Eye Abnormalities / Q000378:metabolism* / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D009363:Neoplasm Proteins; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology*; D051153:Wnt Proteins; D029961:Zebrafish Proteins
D050659:Core Binding Factor Alpha 1 Subunit; D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D011973:Receptors, LDL; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D002118:Calcium