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：
9341894
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 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9341894
关键词：
Biochemical Biological Assay Biology Cartilage Cartilage Diseases Cartilaginous exostosis Cell Proliferation Cell surface Cells Chondrocytes Chondrogenesis Chondrogenic Neoplasm Chondroma Clinical Cytoplasmic Protein Degenerative polyarthritis Development Employee Strikes 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 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 regenerative restoration skeletal skeletal disorder socioeconomics stemness transcription factor tumor tumorigenesis

Biochemical Biological Assay Biology Cartilage Cartilage Diseases Cartilaginous exostosis Cell Proliferation Cell surface Cells Chondrocytes Chondrogenesis Chondrogenic Neoplasm Chondroma Clinical Cytoplasmic Protein Degenerative polyarthritis Development Employee Strikes 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 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 regenerative restoration skeletal skeletal disorder socioeconomics stemness transcription factor tumor tumorigenesis

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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（由适用提供）：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。缺乏关于调节软骨发生的分子和细胞机制的足够知识，主要导致这种情况。该提案的目的试图通过研究软骨的发育和软骨的发育和体内稳定性如何受到表达软骨软骨祖细胞（CCP）的新确定的人群的调节和细胞质蛋白质酪氨酸酪氨酸磷酸酶SHP2（由PTPNENCODN）的调节。在最近的一项旨在表征表达CTSK细胞中缺乏SHP2的小鼠的骨骼表型的研究中，我们做出了两个重要且相互关联的发现（Nature，2013。499：491-5）。首先，我们确定了一个新的CCP人群，主要位于Ranvier的围齿凹槽中，并且在关节和生长板软骨中也稀疏散布。 CCP表达间充质干细胞（MSC）表面标记，似乎在软骨发育和稳态中起作用。其次，我们发现SHP2在软骨中充当肿瘤抑制剂：CCP中小鼠的SHP2缺失可产生惊人的骨骼表型，以骨骼内核瘤和骨中的邻肌瘤的生长。这些骨骼疾病概括了Metachromatics的临床特征，这是人类软骨肿瘤综合征，其中杂合SHP2功能丧失（LOF）突变已被鉴定出来。我们的发现强烈表明，CCP是一个在功能上和功能上不同的软骨干细胞中，而SHP2是CCP的关键调节剂，在软骨发生过程中可能是其他软骨细胞的调节剂。与在这种情况下有关蛋白质酪氨酸激酶信号的大量文献相反，SHP2在软骨发生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通过影响主要软骨转录因子SOX9的表达和转录活性来调节CCP和软骨发生的脂肪决策。 SHP2缺乏导致SOX9表达和转录活性的改变会导致过度的细胞增殖，分化和软骨性肿瘤。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。 SHP2如何调节软骨生成和SHP2损失的杂合性突变会导致软骨肿瘤发生。我们的长期目标是制定策略来抑制软骨变性，并通过动员CCP和/或修改SHP2调节的信号通路（S）来促进其再生和稳态。这项研究的结果将为从肿瘤到骨关节炎的新疗法发展和再生方法的发展提供新的启示。