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

• 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
• 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

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信号传导是骨形成的稳健调节剂，并且被Lrp共受体拮抗剂如硬化蛋白（Sost）拮抗。转化生长因子-β（TGF？）显示多效性和看似矛盾的影响骨形成：TGF？刺激骨祖细胞迁移和增殖，但也抑制 基质矿化并促进机械性下编织骨的形成。我们最近已经证明，TGF？通过I型受体Alk5增加Sost的表达，并提出TGF？通过增加Wnt共受体拮抗剂Sost的表达来抑制Wnt信号传导，可以间接地抑制骨量。此外，我们表明，刺激转录的TGF？在Sost上的表达是由Sost远端增强子元件ECR 5介导的，而不是Sost近端启动子。在这个提议中，（1）我们将检查Alk5缺失或组成性激活对成熟成骨细胞和骨细胞的影响，并检查Alk5缺失或激活对成年小鼠骨骼表型的影响。(2)一旦我们确定了负责介导Alk5对骨骼影响的细胞类型（成骨细胞或骨细胞），我们将检查Alk5对Sost和Wnt信号传导表达的影响，并使用功能丧失或获得的Sost模型，确定Alk5对骨骼表型的调节依赖于Sost的程度。(3)最后，我们将研究Alk5和Sost增强子ECR 5对已知负荷诱导的Sost表达减少的贡献。虽然已经付出了很大的努力，以确定一个单一的骨形成因子的影响，我们的建议，旨在确定如何之间的相互作用TGF？和Wnt信号可以解释TGF？并开始鉴定用于药物驱动的骨修复和骨固定的新的药理学靶点。