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

TGFb-ALK5 在骨中 Wnt 信号传导和力转导中的整合

基本信息

批准号：
8690769
负责人：
DAMIAN C GENETOS
金额：
$ 33万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8690769
关键词：
Address Adult Age-Related Bone Loss American Anabolism Biological Assay Bone Matrix Bone Regeneration Breeding Complex Data Disease Distal Distal Enhancer Elements Enhancers Event Exhibits Fracture Genetic Transcription Goals Homeostasis Hormones Immature Bone In Vitro Inferior Lead Longevity Mechanics Mediating Mediator of activation protein Medical Modeling Molecular Mus Mutation Osteoblasts Osteocytes Osteogenesis Osteoporosis Parathyroid gland Phenotype Property Quality of life Regulation Role Signal Pathway Signal Transduction Skeletal Development Skeleton Small Interfering RNA Stimulus TGF-beta type I receptor Testing Transcriptional Regulation Transforming Growth Factor beta bone bone mass bone metabolism bone quality cell type cost fluid flow gain of function in vivo inhibitor/antagonist interest loss of function migration mineralization novel novel strategies osteoblast differentiation osteoprogenitor cell overexpression promoter public health relevance receptor repaired skeletal socioeconomics ulna

项目摘要

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.

描述（由申请人提供）：Wnt信号传导是骨骼形成的强大调节剂，并由LRP共受体拮抗剂（如Sclerostin（Sost））拮抗。转化生长因子β（TGF？）对骨形成的多效性和看似矛盾的影响：TGF？刺激骨基因生成剂 - 迁移和增殖，但也抑制了基质矿化并促进机械内部编织骨的形成。我们最近证明了TGF？通过I型受体ALK5提高SOST的表达，并提出TGF？通过增加Wnt共受体拮抗剂SOST的表达，可以通过抑制Wnt信号传导间接抑制骨骼质量。此外，我们证明了TGF的刺激转录效应？在SOST上较长的远端增强子元件ECR5介导，而不是较高的近端启动子。在此提案中，（1）我们将检查成熟成骨细胞和骨细胞中Alk5缺失或本构激活的影响，并检查成年小鼠中ALK5缺失或激活对骨骼表型的影响。 (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）最后，我们将研究ALK5和SOST增强子ECR5对已知负载诱导的SOST表达减少的贡献。尽管已经付出了很多努力来确定奇异骨质因子对骨骼形成的影响的影响，但我们的建议试图确定TGF之间的相互作用？ Wnt信号传导可以解释TGF的分化依赖性效应？在骨骼上，开始确定用于药物驱动的骨修复和合成代谢的新型药理靶标。