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¹ Department of Molecular and Cellular Biology and Medicine, Baylor College of Medicine, Houston, TX 77030
² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030
³ Department Pathology, Baylor College of Medicine, Houston, TX 77030
⁴ Division of Developmental Biology, Department of Ophthalmology, Children's Hospital Research Foundation, University of Cincinnati, Cincinnati, OH 45229
⁵ Department of Genetics, Harvard Medical School, Boston, MA 02115

Address correspondence to Gerard Karsenty or Lawrence Chan, Baylor College of Medicine, One Baylor Plaza, Rm. S921, Houston, TX 77030. Tel.: (713) 798-4490. Fax: (713) 798-1530. E-mail: karsenty{at}bcm.tmc.edu or lchan{at}bcm.tmc.edu

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.

Key Words: low bone mass; blindness; Wnt; osteoblast function; vascular regression

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• Mercurio, S., Latinkic, B., Itasaki, N., Krumlauf, R., Smith, J. C. (2004). Connective-tissue growth factor modulates WNT signalling and interacts with the WNT receptor complex. Development 131: 2137-2147 [Abstract] [Full Text]  
• He, X., Semenov, M., Tamai, K., Zeng, X. (2004). LDL receptor-related proteins 5 and 6 in Wnt/{beta}-catenin signaling: Arrows point the way. Development 131: 1663-1677 [Abstract] [Full Text]  
• Long, F., Chung, U.-i., Ohba, S., McMahon, J., Kronenberg, H. M., McMahon, A. P. (2004). Ihh signaling is directly required for the osteoblast lineage in the endochondral skeleton. Development 131: 1309-1318 [Abstract] [Full Text]  
• Roman-Roman, S., Shi, D.-L., Stiot, V., Hay, E., Vayssiere, B., Garcia, T., Baron, R., Rawadi, G. (2004). Murine Frizzled-1 Behaves as an Antagonist of the Canonical Wnt/{beta}-Catenin Signaling. J. Biol. Chem. 279: 5725-5733 [Abstract] [Full Text]  
• Tian, E., Zhan, F., Walker, R., Rasmussen, E., Ma, Y., Barlogie, B., Shaughnessy, J. D. Jr. (2003). The Role of the Wnt-Signaling Antagonist DKK1 in the Development of Osteolytic Lesions in Multiple Myeloma. NEJM 349: 2483-2494 [Abstract] [Full Text]  
• Cheng, S.-L., Shao, J.-S., Charlton-Kachigian, N., Loewy, A. P., Towler, D. A. (2003). Msx2 Promotes Osteogenesis and Suppresses Adipogenic Differentiation of Multipotent Mesenchymal Progenitors. J. Biol. Chem. 278: 45969-45977 [Abstract] [Full Text]  
• Caricasole, A., Ferraro, T., Iacovelli, L., Barletta, E., Caruso, A., Melchiorri, D., Terstappen, G. C., Nicoletti, F. (2003). Functional Characterization of WNT7A Signaling in PC12 Cells: INTERACTION WITH A FZD5{middle dot}LRP6 RECEPTOR COMPLEX AND MODULATION BY DICKKOPF PROTEINS. J. Biol. Chem. 278: 37024-37031 [Abstract] [Full Text]  
• Shui, Y.-B., Wang, X., Hu, J. S., Wang, S.-P., Garcia, C. M., Potts, J. D., Sharma, Y., Beebe, D. C. (2003). Vascular Endothelial Growth Factor Expression and Signaling in the Lens. IOVS 44: 3911-3919 [Abstract] [Full Text]  
• Liu, G., Bafico, A., Harris, V. K., Aaronson, S. A. (2003). A Novel Mechanism for Wnt Activation of Canonical Signaling through the LRP6 Receptor. Mol. Cell. Biol. 23: 5825-5835 [Abstract] [Full Text]  
• Kawano, Y., Kypta, R. (2003). Secreted antagonists of the Wnt signalling pathway. J. Cell Sci. 116: 2627-2634 [Abstract] [Full Text]  
• Yu, K., Xu, J., Liu, Z., Sosic, D., Shao, J., Olson, E. N., Towler, D. A., Ornitz, D. M. (2003). Conditional inactivation of FGF receptor 2 reveals an essential role for FGF signaling in the regulation of osteoblast function and bone growth. Development 130: 3063-3074 [Abstract] [Full Text]  

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