Wnt signaling is a robust regulator of bone formation, and is antagonized by Lrp co-receptor antagonists like Sclerostin (Sost). Transforming growth factor-beta (TGF) exhibits pleiotropic and seemingly contradictory effects upon bone formation: TGF stimulates osteoprogenitor - migration and proliferation, but is also inhibitory to matrix mineralization and promotes formation of mechanically-inferior woven bone. We have recently demonstrated that TGF increases expression of Sost through the type I receptor Alk5, and propose that TGF inhibition of bone mass may occur indirectly via inhibition of Wnt signaling by increasing expression of the Wnt co-receptor antagonist Sost. Further, we demonstrated that the stimulatory transcriptional effects of TGF upon Sost are mediated by the Sost distal enhancer element ECR5, and not the Sost proximal promoter. Within this proposal, (1) we will examine the influence of Alk5 deletion or constitutive activation in mature osteoblasts and osteocytes, and examine the influence of Alk5 deletion or activation upon skeletal phenotype in adult mice. (2) Once we have identified the cell type (osteoblast or osteocyte) responsible for mediating the influence of Alk5 upon the skeleton, we will examine the influence of Alk5 upon expression of Sost and Wnt signaling, and, using Sost models with loss or gain of function, identify the degree to which Alk5 regulation of skeletal phenotype is dependent upon Sost. (3) Finally, we will examine the contribution of Alk5 and the Sost enhancer ECR5 to known load-induced reductions in Sost expression. While much effort has been exerted into identifying the influence of a singular osteotropic factor's influence upon bone formation, our proposal seeks to identify how interplay between TGF and Wnt signaling may explain the differentiation-dependent effects of TGF upon the skeleton and begin to identify novel pharmacologic targets for pharmaceutically-driven bone repair and anabolism.

Public Health Relevance

There is no cure for age-related osteoporosis, which predisposes to bone fractures and decreased quality of life. Identifying the mechanisms involved in suppression of bone formation by endogenous inhibitors will likely lead to novel approaches to enhance bone formation under disease states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR064255-05
Application #
9297225
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Nicks, Kristy
Project Start
2013-07-01
Project End
2019-06-30
Budget Start
2017-07-01
Budget End
2019-06-30
Support Year
5
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of California Davis
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Loots, Gabriela G; Robling, Alexander G; Chang, Jiun C et al. (2018) Vhl deficiency in osteocytes produces high bone mass and hematopoietic defects. Bone 116:307-314
Robling, Alexander G; Kang, Kyung Shin; Bullock, Whitney A et al. (2016) Sost, independent of the non-coding enhancer ECR5, is required for bone mechanoadaptation. Bone 92:180-188
Wong, Alice; Loots, Gabriela G; Yellowley, Clare E et al. (2015) Parathyroid hormone regulation of hypoxia-inducible factor signaling in osteoblastic cells. Bone 81:97-103
Khorasani, Mohammad S; Diko, Sindi; Hsia, Allison W et al. (2015) Effect of alendronate on post-traumatic osteoarthritis induced by anterior cruciate ligament rupture in mice. Arthritis Res Ther 17:30
Heffner, M A; Anderson, M J; Yeh, G C et al. (2014) Altered bone development in a mouse model of peripheral sensory nerve inactivation. J Musculoskelet Neuronal Interact 14:1-9
Chahine, Nadeen O; Collette, Nicole M; Thomas, Cynthia B et al. (2014) Nanocomposite scaffold for chondrocyte growth and cartilage tissue engineering: effects of carbon nanotube surface functionalization. Tissue Eng Part A 20:2305-15