Integration of TGFb-ALK5 on Wnt signaling and mechanotransduction in bone

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): 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.
StatusFinished
Effective start/end date7/1/136/30/18

Funding

  • National Institutes of Health: $357,414.00
  • National Institutes of Health: $324,731.00
  • National Institutes of Health: $329,989.00
  • National Institutes of Health: $336,288.00

ASJC

  • Medicine(all)

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