Osteoporosis pseudoglioma (OPPG), a human syndrome characterized by extremely low bone density, is caused by a deficiency in the Wnt co-receptor LRP5. Point mutations in this same receptor cause high bone mass by encoding for proteins with inappropriate signaling activity. The highly related LRP6 protein also influences bone mass. Given the intense interest in translating these findings into therapies to treat low bone mass, there is a critical need to understand how LRP5 and LRP6 protein control bone growth. Both LRP5 and LRP6 can transduce signals from Wnt ligands resulting in stabilization of (-catenin in the cytosol. To assess whether altered regulation of (-catenin underlies the phenotypes in humans an mice carrying mutated LRP5 and LRP6 genes, we and others have created mouse models in which the (-catenin gene was deleted at specific stages of osteoblast differentiation. We used osteocalcin-cre (OC-cre) to delete (-catenin in differentiated osteoblasts. OC-cre;(-cateninflox/flox mice die by one month of age, have elevated numbers of osteoclasts, and display severely low bone mass. Ablation of (-catenin in osteochondral precursors by Dermo1-cre blocks osteoblast differentiation and enhances chondrogenesis. In both cases, the phenotype of (-catenin ablation is much more severe than that of a global Lrp5 knockout. One explanation for difference in phenotypic severity between loss of p-catenin and deletion of Lrp5 is that Lrp6 can also regulate p-catenin in osteoblasts. In this proposal we examine the roles of Lrp6 and Lrp5 in early (commitment) and late stages of osteoblast differentiation. We predict that ablation of either Lrp5 or Lrp6 will have unique consequences at these stages, and that loss of both genes will cause more severe phenotypes. Relevant to Public Health: Addressing these questions has overarching implications: Figuring out how these receptors work will help to identify and validate novel targets and develop novel strategies for how to treat low bone mass as well as provide important insights into how the Wnt signaling pathway controls bone development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR053293-05
Application #
8114152
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Chen, Faye H
Project Start
2007-08-10
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
5
Fiscal Year
2011
Total Cost
$355,586
Indirect Cost
Name
Van Andel Research Institute
Department
Type
DUNS #
129273160
City
Grand Rapids
State
MI
Country
United States
Zip Code
49503
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Zhong, Zhendong A; Zahatnansky, Juraj; Snider, John et al. (2015) Wntless spatially regulates bone development through ?-catenin-dependent and independent mechanisms. Dev Dyn 244:1347-55
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Collins, Caitlyn J; Vivanco, Juan F; Sokn, Scott A et al. (2015) Fracture healing in mice lacking Pten in osteoblasts: a micro-computed tomography image-based analysis of the mechanical properties of the femur. J Biomech 48:310-7
Cheng, Su-Li; Ramachandran, Bindu; Behrmann, Abraham et al. (2015) Vascular smooth muscle LRP6 limits arteriosclerotic calcification in diabetic LDLR-/- mice by restraining noncanonical Wnt signals. Circ Res 117:142-56

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