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Role of PTPN11 in Cartilage Stem Cells and Tumorigenesis

PTPN11 在软骨干细胞和肿瘤发生中的作用

基本信息

批准号：
9766824
负责人：
Wentian Yang
金额：
$ 35.42万
依托单位：
RHODE ISLAND HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-21 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9766824
关键词：
Biochemical Biological Biological Assay Biology Cartilage Cartilage Diseases Cartilaginous exostosis Cell Proliferation Cell surface Cells Chondrocytes Chondrogenesis Chondrogenic Neoplasm Chondroma Clinical Cytoplasmic Protein Degenerative polyarthritis Development Epiphysial cartilage Foundations Genetic Transcription Goals Growth Homeostasis Human In Vitro Knowledge Lead Light Literature Loss of Heterozygosity Marrow Mediating Mesenchymal Stem Cells Metachondromatosis Mitotic Modeling Molecular Mus Musculoskeletal Diseases Mutagenesis Mutation Natural regeneration Nature Outcome Study PTPN11 gene Phenotype Phosphorylation Play Population Post-Translational Protein Processing Property Protein Tyrosine Kinase Protein Tyrosine Phosphatase Quantitative Reverse Transcriptase PCR Role SOX9 protein Signal Pathway Signal Transduction Stem cells Sushi Domain Syndrome Transcript Tumor Suppressor Proteins Work bone cartilage degradation cartilage development cathepsin K cost healing in vivo long bone loss of function mutation migration novel novel therapeutics progenitor promoter public health relevance recruit regenerative restoration skeletal skeletal disorder socioeconomics stemness transcription factor tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Cartilage diseases remain among the most costly musculoskeletal disorders, their treatment continues to be a major clinical challenge. Lack of adequate knowledge regarding the molecular and cellular mechanisms that regulate chondrogenesis primarily causes this scenario. The goal of this proposal attempts to fill this knowledge gap by studying how the development and homeostasis of cartilage are regulated by the newly identified population of cathepsin K (Ctsk)-expressing chondroid progenitors (CCP) and by the cytoplasmic protein tyrosine phosphatase SHP2 (encoded by PTPN11). In a recent study aimed at characterizing the skeletal phenotype of mice lacking SHP2 in Ctsk- expressing cells, we made two important and interrelated discoveries (Nature, 2013. 499:491-5). First, we identified a novel population of CCP which primarily reside in the perichondrial groove of Ranvier and also sparsely scatter in articular and growth plate cartilage. CCP express mesenchymal stem cell (MSC) surface markers and appear to play a role in cartilage development and homeostasis. Second, we found that SHP2 functions as a tumor suppressor in cartilage: SHP2 deletion in CCP in mice yields a striking skeletal phenotype, featuring the growth of osteochondromas and enchondromas in bone. These skeletal diseases recapitulate the clinical features of metachondromatosis, a cartilage tumor syndrome in humans in which heterozygous SHP2 loss-of-function (LOF) mutations have been identified. Our findings strongly suggest that CCP are a phenotypically and functionally distinct pool of cartilage stem cells, and SHP2 is a key modulator of CCP and possibly other chondroid cells during chondrogenesis. Little is known about the regulatory role of SHP2 in chondrogenesis and cartilage homeostasis, in contrast to the vast literature regarding protein tyrosine kinase signaling in this context. We hypothesize that CCP are cartilage stem cells; SHP2 regulates fate decisions of CCP and chondrogenesis by influencing the expression and transcriptional activity of the master chondrogenic transcription factor SOX9. Altered SOX9 expression and transcriptional activity as a result of SHP2 deficiency can cause excessive cell proliferation, differentiation and cartilaginous neoplasm. The specific objectives of this proposal are to determine CCP, to what extent, are truly cartilage stem cells; and mechanistically how SHP2 regulates chondrogenesis and SHP2 loss-of-heterozygosity mutations cause cartilage tumorigenesis. Our long-term objective is to develop strategies to inhibit cartilage degeneration and promote its regeneration and homeostasis by mobilizing CCP and/or modifying SHP2-regulated signaling pathway(s). The outcome of this study will shed new light on the development of novel therapeutics and regenerative approaches to a spectrum of cartilage diseases, from tumors to osteoarthritis.

描述（由申请人提供）：软骨疾病仍然是最昂贵的肌肉骨骼疾病之一，其治疗仍然是主要的临床挑战。对调节软骨形成的分子和细胞机制缺乏足够的了解是造成这种情况的主要原因。该提案的目标是通过研究新鉴定的表达组织蛋白酶 K (Ctsk) 的软骨样祖细胞 (CCP) 群体和细胞质蛋白酪氨酸磷酸酶 SHP2（由 PTPN11 编码）如何调节软骨的发育和稳态，从而填补这一知识空白。在最近一项旨在表征 Ctsk 表达细胞中缺乏 SHP2 的小鼠骨骼表型的研究中，我们做出了两项重要且相互关联的发现 (Nature, 2013. 499:491-5)。首先，我们发现了一个新的 CCP 群体，它主要存在于 Ranvier 软骨膜沟中，也稀疏地分散在关节软骨和生长板软骨中。 CCP 表达间充质干细胞 (MSC) 表面标记，似乎在软骨发育和体内平衡中发挥作用。其次，我们发现SHP2在软骨中起到肿瘤抑制因子的作用：小鼠CCP中SHP2的缺失产生了惊人的骨骼表型，其特征是骨中骨软骨瘤和内生软骨瘤的生长。这些骨骼疾病概括了多软骨瘤病的临床特征，多软骨瘤病是一种人类软骨肿瘤综合征，其中已鉴定出杂合的 SHP2 功能丧失 (LOF) 突变。我们的研究结果强烈表明，CCP 是表型和功能不同的软骨干细胞库，而 SHP2 是 CCP 和可能的其他软骨样细胞在软骨形成过程中的关键调节剂。与此方面有关蛋白酪氨酸激酶信号传导的大量文献相反，人们对 SHP2 在软骨形成和软骨稳态中的调节作用知之甚少。我们假设CCP是软骨干细胞； SHP2 通过影响主要软骨形成转录因子 SOX9 的表达和转录活性来调节 CCP 和软骨形成的命运决定。 SHP2 缺陷导致 SOX9 表达和转录活性改变，可导致细胞过度增殖、分化和软骨肿瘤。该提案的具体目标是确定CCP在多大程度上是真正的软骨干细胞；以及SHP2如何调节软骨形成以及SHP2杂合性缺失突变导致软骨肿瘤发生的机制。我们的长期目标是制定策略，通过动员 CCP 和/或修改 SHP2 调节的信号通路来抑制软骨退化并促进其再生和稳态。这项研究的结果将为从肿瘤到骨关节炎等一系列软骨疾病的新型疗法和再生方法的开发提供新的线索。