Wnt signaling has emerged as a major target pathway for developing novel bone anabolic agents. Although promising therapeutics has entered clinical trials, our understanding about how Wnt signaling promotes bone anabolism remains incomplete. Nonetheless, a fundamental understanding of the mechanism is critical for rational design of the next generation of therapies. We have previously discovered that Wnt signaling reprograms cellular metabolism during osteoblast differentiation. In particular, Wnt stimulates both aerobic glycolysis and glutaminolysis. We have further demonstrated that the increase in glutaminolysis fulfills both energetic and biosynthetic needs of osteoblasts. Moreover, redirecting glycolysis away from lactate production with a small molecule diminishes Wnt-induced bone formation. However, it remains unknown how the glycolytic switch favoring lactate production contributes to bone anabolism in response to Wnt. Here we test the central hypothesis that Wnt-induced aerobic glycolysis promotes bone formation through stimulation of glutaminolysis. We test the hypothesis in three specific aims.
Aim 1 genetically tests the effect of Ldha deletion on osteosclerosis caused by a mutation of Lrp5 in mice.
Aim 2 specifically examines the relationship between glycolysis and glutaminolysis in both bone explants and primary cell cultures. Finally, in Aim 3 we will determine the efficacy of Ldha overexpression in promoting bone formation in both an ossicle implant model and transgenic mice. Successful completion of the proposal is expected to pave a new avenue for developing bone-enhancing drugs.

Public Health Relevance

There remains a critical need for safe and effective therapies to stimulate bone formation in osteoporotic patients. 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 builds upon our previous discovery that Wnt stimulates both aerobic glycolysis and glutaminolysis in osteoblast-lineage cells, and is designed to establish the role and mechanism of aerobic glycolysis in mediating the bone anabolic function of Wnt proteins. Research results from this study may provide novel molecular targets for developing 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 #
5R01AR060456-10
Application #
9724356
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Nicks, Kristy
Project Start
2018-09-25
Project End
2021-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
10
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19146
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Lee, Seung-Yon; Abel, E Dale; Long, Fanxin (2018) Glucose metabolism induced by Bmp signaling is essential for murine skeletal development. Nat Commun 9:4831
Chen, Jianquan; Long, Fanxin (2018) mTOR signaling in skeletal development and disease. Bone Res 6:1
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
Karner, Courtney M; Long, Fanxin (2017) Wnt signaling and cellular metabolism in osteoblasts. Cell Mol Life Sci 74:1649-1657
Jiang, Ming; Fu, Xuejie; Yang, Huilin et al. (2017) mTORC1 Signaling Promotes Limb Bud Cell Growth and Chondrogenesis. J Cell Biochem 118:748-753
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
Karner, Courtney M; Lee, Seung-Yon; Long, Fanxin (2017) Bmp Induces Osteoblast Differentiation through both Smad4 and mTORC1 Signaling. Mol Cell Biol 37:
Shi, Yu; Long, Fanxin (2017) Hedgehog signaling via Gli2 prevents obesity induced by high-fat diet in adult mice. Elife 6:

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