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Ptpnll deletion in a novel progenitor causes metachondromatosis by inducing hedgehog signalling

机译：新型祖细胞中的Ptpnll缺失通过诱导刺猬蛋白信号传导导致软骨软骨病

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摘要

The tyrosine phosphatase SHP2, encoded by PTPN11, is required for the survival, proliferation and differentiation of various cell types. Germline activating mutations in PTPN11 cause Noonan syndrome, whereas somatic PTPN11 mutations cause childhood myeloproliferative disease and contribute to some solid tumours. Recently, heterozygous inactivating mutations in PTPNU were found in metachondromatosis, a rare inherited disorder featuring multiple exostoses, enchondromas, joint destruction and bony deformities. The detailed pathogenesis of this disorder has remained unclear. Here we use a conditional knockout (floxed) Ptpn11 allele (Ptpnll~(fl)) and Cre recombinase transgenic mice to delete Ptpn11 specifically in monocytes, macrophages and osteoclasts (lysozyme M-Cre; LysMCre) or in cathepsin K (Ctsk)-expressing cells, previously thought to be osteoclasts. LysMCre;Ptpn11~(fl/fl) mice had mild osteopetrosis. Notably, however, CtskCre;Ptpn11~(fl/fl) mice developed features very similar to metachondromatosis. Lineage tracing revealed a novel population of CtskCre-expressing cells in the perichondrial groove of Ranvier that display markers and functional properties consistent with mesenchymal progenitors. Chondroid neoplasms arise from these cells and show decreased extracellular signal-regulated kinase (ERK) pathway activation, increased Indian hedgehog (Ihh) and parathyroid hormone-related protein (Pthrp, also known as Pthlh) expression and excessive proliferation. Shp2-deficient chondroprogenitors had decreased fibroblast growth factor-evoked ERK activation and enhanced Ihh and Pthrp expression, whereas fibroblast growth factor receptor (FGFR) or mitogen-activated protein kinase kinase (MEK) inhibitor treatment of chondroid cells increased Ihh and Pthrp expression. Importantly, smoothened inhibitor treatment ameliorated metachondromatosis features in CtskCre;Ptpn11~（fl/fl) mice. Thus, in contrast to its pro-oncogenic role in haematopoietic and epithelial cells, Ptpn11 is a tumour suppressor in cartilage, acting through a FGFR/MEK/ERK-dependent pathway in a novel progenitor cell population to prevent excessive Ihh production.
机译：PTPN11编码的酪氨酸磷酸酶SHP2是各种细胞类型的存活，增殖和分化所必需的。 PTPN11中的生殖细胞激活突变会导致Noonan综合征，而体细胞PTPN11突变会导致儿童时期的骨髓增生性疾病并导致某些实体瘤。最近，在软骨病中发现了PTPNU中的杂合失活突变，这是一种罕见的遗传性疾病，具有多个外生骨，内生软骨瘤，关节破坏和骨畸形。该疾病的详细发病机理仍不清楚。在这里，我们使用条件敲除（固定）的Ptpn11等位基因（Ptpnll〜（fl））和Cre重组酶转基因小鼠删除Ptpn11，特别是在单核细胞，巨噬细胞和破骨细胞（溶菌酶M-Cre； LysMCre）或组织蛋白酶K（Ctsk）表达中删除Ptpn11细胞，以前被认为是破骨细胞。 LysMCre; Ptpn11〜（fl / fl）小鼠出现轻度骨质疏松。但是，值得注意的是，CtskCre; Ptpn11〜（fl / fl）小鼠的特征与软骨软骨病非常相似。沿袭追踪揭示了在Ranvier的软骨膜沟中表达CtskCre的新型细胞群，这些细胞显示出与间充质祖细胞一致的标志物和功能特性。软骨瘤从这些细胞中产生，并显示出减少的细胞外信号调节激酶（ERK）途径活化，增加的印度刺猬（Ihh）和甲状旁腺激素相关蛋白（Pthrp，也称为Pthlh）表达和过度增殖。缺乏Shp2的软骨生成剂降低了成纤维细胞生长因子引起的ERK激活并增强了Ihh和Pthrp表达，而成纤维细胞生长因子受体（FGFR）或丝裂原激活的蛋白激酶激酶（MEK）抑制剂治疗的软骨细胞则增加了Ihh和Pthrp表达。重要的是，平滑的抑制剂治疗可改善CtskCre; Ptpn11〜（fl / fl）小鼠的软骨软骨病的特征。因此，与它在造血和上皮细胞中的促癌作用相反，Ptpn11是软骨中的肿瘤抑制因子，在新的祖细胞群中通过FGFR / MEK / ERK依赖性途径发挥作用，以防止过量的Ihh产生。

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  • 来源
    《Nature》 |2013年第7459期|491-495|共5页
  • 作者

    Wentian Yang; Jianguo Wang; Douglas C. Moore; Haipei Liang; Mark Dooner; Qian Wu; Richard Terek; Qian Chen; Michael G. Ehrlich; Peter J. Quesenberry; Benjamin G. Neel;

  • 作者单位

    Department of Orthopaedics, Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island 02903, USA;

    Department of Orthopaedics, Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island 02903, USA;

    Department of Orthopaedics, Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island 02903, USA;

    Department of Orthopaedics, Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island 02903, USA;

    Department of Medicine and COBRECenterfor Stem Cell Biology,Rhode Island Hospital and Brown University Alpert Medical School, Providence, Rhode Island 02903, USA;

    Department of Pathology and Laboratory Medicine, University of Connecticut Health Center,Farmington, Connecticut 06030, USA;

    Department of Orthopaedics, Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island 02903, USA;

    Department of Orthopaedics, Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island 02903, USA;

    Department of Orthopaedics, Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island 02903, USA;

    Department of Medicine and COBRECenterfor Stem Cell Biology,Rhode Island Hospital and Brown University Alpert Medical School, Providence, Rhode Island 02903, USA;

    Princess Margaret Cancer Center, University Health Network, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G IL7, Canada;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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