Function and Regulation of Osteonectin in Bone

骨连接素在骨中的功能和调节

• 批准号: 7638315
• 负责人: Anne M Delany
• 金额: $ 31.94万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7638315
• 关键词: 3' Untranslated Regions; Adipocytes; Aging; Basic Science; Bioinformatics; Bone Density; Bone remodeling; Cell Communication; Cell Line; Cell Lineage; Cell Shape; Cells; Characteristics; Class; Clinical Research; Collagen; Collagen Fibril; Commit; Cysteine; Disease; Equilibrium; Extracellular Matrix; Functional RNA; Gene Expression; Genes; Glycoproteins; Goals; Haplotypes; Human; Human Activities; In Vitro; Innate Bone Remodeling; Knock-in Mouse; Knowledge; Malignant Neoplasms; Mammals; Marrow; Mechanics; Mediating; Mesenchymal Stem Cells; MicroRNAs; Modification; Molecular; Mus; Mutation; Numbers; Obesity; Osteoblasts; Osteoclasts; Osteogenesis; Osteonectin; Parathyroid Hormones; Pathology; Phenotype; Play; Process; Property; Proteins; Range; Regulation; Role; Signal Transduction; Single Nucleotide Polymorphism; Skeletal system; Skeleton; Thinking; Tissues; Trans-Activators; Transcript; Translational Repression; Translations; Untranslated Regions; Urination; Work; bone; bone loss; cell behavior; cell type; hormone therapy; human PTH protein; in vivo; knock-down; lipid biosynthesis; migration; response; substantia spongiosa

Bone loss with aging results from imbalanced bone remodeling, with decreased osteoblast number, increased osteoclast number, and increased adipocyte number in the marrow. Mesenchymal stem cells (MSCs) give rise to both osteoblasts and adipocytes, and MSC lineage allocation is altered in aging. MSC lineage allocation is controlled by diverse intracellular signals, cell-cell interactions and the bone microenvironment. The most abundant non-collagen matrix protein in the bone microenvironment is the matricellular glycoprotein osteonectin (secreted protein acidic rich in cysteine, SPARC; BM-40). In the skeleton, osteonectin promotes osteoblast differentiation, suppresses adipogenesis, and regulates the balance between bone formation and resorption in response to PTH treatment. It is highly expressed early in osteoblastic differentiation, but its expression decreases as the cells acquire characteristics of mature osteoblasts. In contrast, osteonectin transcript levels change little during osteoblastic differentiation, indicating regulation at the level of translation. MicroRNAs (miRNAs) are small non-coding RNAs that mediate translational repression by interacting with the 3¿ untranslated region (UTR) of target mRNAs. We found that miR-29a and -29c act on the osteonectin 3¿ UTR and mediate translational repression in committed osteoblasts. We hypothesize that miR-29a and -29c regulate osteoblastic differentiation. Importantly, single nucleotide polymorphisms (SNPs) in the 3¿ UTR of osteonectin gene are associated with bone density in humans, and these SNPs modulate 3¿ UTR function. Since osteonectin is critical for normal bone remodeling and response to bone anabolic PTH therapy, the goal of our work is to understand post-transcriptional mechanisms regulating its expression in the skeleton. We will 1. determine how human osteonectin 3¿ UTR SNPs modulate protein levels during osteoblastic differentiation in vitro; 2. determine the activity of human osteonectin 3¿ UTR haplotypes in vivo, using mice carrying knock-in mutations of the human UTR and 3. determine the role of miR-29 in osteoblast differentiation in vitro. These studies will fill a substantial void in the knowledge of key mechanisms regulating bone mass. In addition, the information we acquire could be applied to other diseases in which osteonectin is thought to play a role in pathology, such as obesity and cancer. This proposal contains basic and translational components, and we will obtain information relevant to both basic science and clinical studies.

骨骼流失随老化而导致的骨重塑不平衡，成骨细胞数量提高，增加 破骨细胞数，骨髓中的脂肪细胞数增加。间充质干细胞（MSC）产生 对于成骨细胞和脂肪细胞，衰老中的MSC谱系分配都发生了变化。 MSC谱系分配是 由潜水的细胞内信号，细胞 - 细胞相互作用和骨微环境控制。最多 骨微环境中富含非胶原基质蛋白是基质糖蛋白 骨蛋白酶（分泌的蛋白质酸性富含半胱氨酸，SPARC； BM-40）。在骨骼中，奥司孔素促进 成骨细胞分化，抑制脂肪形成，并调节骨形成和 响应PTH治疗的解析。它在成骨细胞分化的早期表现出色，但 表达会随着细胞获得成熟成骨细胞的特征而降低。相比之下，骨质蛋白 成骨细胞分化期间的转录水平很小，表明在翻译水平下进行调节。 microRNA（miRNA）是小型非编码RNA，通过与 3靶标mRNA的未翻译区域（UTR）。我们发现miR -29a和-29c对骨蛋白丝蛋白3的作用 并介导成骨细胞中的翻译表达。我们假设miR -29a和-29c 调节成骨细胞分化。重要的是，在3 utr中的单核苷酸多态性（SNP） Osteonectin基因与人类的骨密度相关，这些SNP调节3 utr功能。 由于骨蛋白对于正常的骨重塑和对骨合成代谢PTH疗法的反应至关重要，因此 我们的工作是了解调节其在骨骼中表达的转录后机制。我们将 1。确定人骨蛋白破坏素3 utth snps在成骨细胞分化过程中如何调节蛋白质水平 体外; 2。使用携带敲入的小鼠在体内确定人骨蛋白切除素3 utr单倍型的活性 人UTR和3的突变。确定miR-29在体外成骨细胞分化中的作用。这些 研究将填补有关调节骨骼质量的关键机制的实质性空隙。另外， 我们获取的信息可以应用于其他疾病，其中骨蛋白丝素被认为在其中发挥作用 病理，例如观察和癌症。该建议包含基本和翻译的组件，我们 将获得与基础科学和临床研究相关的信息。