Wnt signaling provides a promising target pathway for developing novel bone anabolic agents. Most studies to date have supported a model in which autocrine or paracrine Wnt signaling in osteoblast-lineage cells directly controls osteoblast biology. This model however, was challenged by a recent study that concluded that LRP5, a co-receptor for Wnt proteins, does not function directly in osteoblasts, but rather through regulating enteric production of serotonin. This study therefore has cast uncertainty about the physiological relevance of direct Wnt signaling in bone. A major cause for the uncertainty is that genetic deletion of ?-catenin (an obligatory effector of canonical Wnt signaling) in osteoblasts by 2.3Col1-Cre did not affect osteoblast number or function in postnatal animals. However, previous work in the mouse embryo indicates that Wnt/Lrp5/?-catenin signaling may function at a stage before 2.3Col1-Cre becomes active. Directly testing this notion in postnatal life has not been feasible because of the lack of proper genetic tools. We have now developed a novel Tet-on system that allows for gene manipulation in osteoprogenitors specifically in postnatal mice. Therefore, we propose to delete ?-catenin in osteoprogenitors postnatally to test the hypothesis that ?-catenin directly regulates bone formation in postnatal life (Aim 1). A second critical barrier to progress in the field is the lack of understanding of the molecular mechanisms that mediate Wnt function in osteoblast-lineage cells. Research has been hindered by the lack of a robust mouse model in which a Wnt protein can be manipulated and assessed for its acute signaling ability in vivo. We have now developed such a model wherein a potent bone anabolic Wnt ligand can be activated in a controlled manner. Therefore, in Aims 2 and 3, we will employ this new mouse model to investigate both biochemically and genetically the signal transduction mechanisms through which Wnt7b induces bone formation in vivo.

Public Health Relevance

Novel strategies are required to safely promote bone formation to treat osteoporosis. Wnt signaling has been known to stimulate bone formation and provides a promising target pathway for developing novel bone anabolic agents, but the underlying molecular mechanisms are not well understood. This proposal is designed to understand the mechanism responsible for the potent bone-stimulating function of Wnt proteins. Research results from this study will provide a molecular framework for developing novel bone-enhancing pharmaceutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR060456-02
Application #
8145639
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Chen, Faye H
Project Start
2010-09-20
Project End
2015-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
2
Fiscal Year
2011
Total Cost
$389,550
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
He, Guangxu; Shi, Yu; Lim, Joohyun et al. (2017) Differential involvement of Wnt signaling in Bmp regulation of cancellous versus periosteal bone growth. Bone Res 5:17016
Jiang, Ming; Fu, Xuejie; Yang, Huilin et al. (2017) mTORC1 Signaling Promotes Limb Bud Cell Growth and Chondrogenesis. J Cell Biochem 118:748-753
Karner, Courtney M; Long, Fanxin (2017) Wnt signaling and cellular metabolism in osteoblasts. Cell Mol Life Sci 74:1649-1657
Karner, Courtney M; Long, Fanxin (2017) Glucose metabolism in bone. Bone :
Shi, Yu; He, Guangxu; Lee, Wen-Chih et al. (2017) Gli1 identifies osteogenic progenitors for bone formation and fracture repair. Nat Commun 8:2043
Lee, Wen-Chih; Guntur, Anyonya R; Long, Fanxin et al. (2017) Energy Metabolism of the Osteoblast: Implications for Osteoporosis. Endocr Rev 38:255-266
Shi, Yu; Long, Fanxin (2017) Hedgehog signaling via Gli2 prevents obesity induced by high-fat diet in adult mice. Elife 6:
Lim, Joohyun; Burclaff, Joseph; He, Guangxu et al. (2017) Unintended targeting of Dmp1-Cre reveals a critical role for Bmpr1a signaling in the gastrointestinal mesenchyme of adult mice. Bone Res 5:16049
Karner, Courtney M; Lee, Seung-Yon; Long, Fanxin (2017) Bmp Induces Osteoblast Differentiation through both Smad4 and mTORC1 Signaling. Mol Cell Biol 37:
Lim, Joohyun; Shi, Yu; Karner, Courtney M et al. (2016) Dual function of Bmpr1a signaling in restricting preosteoblast proliferation and stimulating osteoblast activity in mouse. Development 143:339-47

Showing the most recent 10 out of 25 publications