SHP2 regulates chondrocyte terminal differentiation, growth plate architecture and skeletal cell fates.
SHP2 regulates chondrocyte terminal differentiation, growth plate architecture and skeletal cell fates.
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DOI：
10.1371/journal.pgen.1004364
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发表时间：
2014
期刊：
影响因子：
4.5
通讯作者：
Warman ML
中科院分区：
文献类型：
--
作者：
Bowen ME;Ayturk UM;Kurek KC;Yang W;Warman ML
在小鼠或人类异软骨瘤病（MC）患者中PTPN 11/SHP 2的缺失导致骨表面（外生骨疣）和骨内（内生软骨瘤）的良性软骨肿瘤。为了阐明软骨肿瘤形成的机制，我们研究了SHP 2在软骨细胞的特化、成熟和组织化中的作用。首先，我们通过对原代软骨细胞沉淀培养物进行RNA-seq来研究软骨细胞成熟。我们发现，SHP 2耗竭，或ERK 1/2通路的抑制，延迟软骨细胞从早期肥大到晚期肥大阶段的终末分化。其次，我们研究了软骨细胞中Ptpn 11在出生后失活的小鼠中的软骨细胞成熟和组织。我们发现，这些小鼠的椎骨生长板具有尚未终末分化的早期肥大软骨细胞的扩展域，并且它们的内生软骨瘤样病变源于由于成熟和骨化区组织的破坏而从生长板移位的软骨细胞。此外，我们观察到，病变从人类MC患者也显示紊乱的软骨细胞成熟区。接下来，我们发现表达Fsp 1-Cre的成纤维细胞中Ptpn 11的失活诱导外生骨疣样增生，这表明骨表面和骨韧带附着部位细胞中SHP 2的缺失诱导异位软骨形成。最后，我们进行了谱系追踪，以显示小鼠的外生骨疣和内生软骨瘤可能含有野生型和SHP 2缺陷型软骨细胞的混合物。总之，这些数据表明，在患有MC的患者中，他们是遗传性PTPN 11功能丧失突变的杂合子，PTPN 11中的二次突变可以通过破坏组织和延迟生长板软骨细胞的终末分化来诱导内生软骨瘤，并且可以通过引起骨表面细胞的异位软骨形成来诱导外生骨疣。此外，数据与来自SHP 2缺陷细胞的旁分泌信号传导一致，所述旁分泌信号传导导致SHP 2充足的细胞被并入病变中。患有遗传性疾病，即异软骨瘤病（MC）的患者在儿童时期会发生多发性良性软骨肿瘤。MC患者在PTPN 11基因中携带杂合的功能丧失突变，并且当第二个PTPN 11等位基因由于体细胞突变而丢失时，他们的软骨肿瘤可能会出现。PTPN 11编码一种称为SHP 2的磷酸酶，该磷酸酶参与多种信号传导途径。在这里，我们使用小鼠模型和细胞培养试验来研究SHP 2的缺失促进软骨肿瘤形成的机制。我们发现，软骨肿瘤，形成骨内（内生软骨瘤）可能会出现由于生长板软骨细胞的生长紊乱和延迟的终末分化，而软骨肿瘤，形成骨表面（外生骨疣）可能会出现由于异位成纤维细胞样细胞的软骨形成骨周围。我们还认为，旁分泌信号从SHP 2缺陷的细胞导致邻近的SHP 2足够的细胞，有助于外生骨疣和内生软骨瘤。最后，我们提供的体外数据表明，ERK 1/2途径受SHP 2调节，并促进软骨细胞终末分化。总之，我们的数据提供了深入了解软骨肿瘤形成的机制，并暗示SHP 2是软骨细胞特化，组织和成熟的关键调节因子。
Loss of PTPN11/SHP2 in mice or in human metachondromatosis (MC) patients causes benign cartilage tumors on the bone surface (exostoses) and within bones (enchondromas). To elucidate the mechanisms underlying cartilage tumor formation, we investigated the role of SHP2 in the specification, maturation and organization of chondrocytes. Firstly, we studied chondrocyte maturation by performing RNA-seq on primary chondrocyte pellet cultures. We found that SHP2 depletion, or inhibition of the ERK1/2 pathway, delays the terminal differentiation of chondrocytes from the early-hypertrophic to the late-hypertrophic stage. Secondly, we studied chondrocyte maturation and organization in mice with a mosaic postnatal inactivation of Ptpn11 in chondrocytes. We found that the vertebral growth plates of these mice have expanded domains of early-hypertrophic chondrocytes that have not yet terminally differentiated, and their enchondroma-like lesions arise from chondrocytes displaced from the growth plate due to a disruption in the organization of maturation and ossification zones. Furthermore, we observed that lesions from human MC patients also display disorganized chondrocyte maturation zones. Next, we found that inactivation of Ptpn11 in Fsp1-Cre-expressing fibroblasts induces exostosis-like outgrowths, suggesting that loss of SHP2 in cells on the bone surface and at bone-ligament attachment sites induces ectopic chondrogenesis. Finally, we performed lineage tracing to show that exostoses and enchondromas in mice likely contain mixtures of wild-type and SHP2-deficient chondrocytes. Together, these data indicate that in patients with MC, who are heterozygous for inherited PTPN11 loss-of-function mutations, second-hit mutations in PTPN11 can induce enchondromas by disrupting the organization and delaying the terminal differentiation of growth plate chondrocytes, and can induce exostoses by causing ectopic chondrogenesis of cells on the bone surface. Furthermore, the data are consistent with paracrine signaling from SHP2-deficient cells causing SHP2-sufficient cells to be incorporated into the lesions. Patients with the inherited disorder, metachondromatosis (MC), develop multiple benign cartilage tumors during childhood. MC patients carry heterozygous loss-of-function mutations in the PTPN11 gene, and their cartilage tumors likely arise when the second PTPN11 allele is lost due to a somatic mutation. PTPN11 encodes a phosphatase called SHP2 that is involved in a variety of signaling pathways. Here, we use mouse models and cell culture assays to investigate the mechanisms by which loss of SHP2 promotes cartilage tumor formation. We show that cartilage tumors that form inside bones (enchondromas) likely arise due to disorganized growth and delayed terminal differentiation of growth plate chondrocytes, while cartilage tumors that form on the bone surface (exostoses) can arise due to ectopic chondrogenesis of fibroblast-like cells that surround bones. We also suggest that paracrine signals from SHP2-deficient cells cause neighboring SHP2-sufficient cells to contribute to exostoses and enchondromas. Finally, we provide in vitro data that the ERK1/2 pathway is regulated by SHP2 and promotes chondrocyte terminal differentiation. Together, our data provide insight into the mechanisms underlying cartilage tumor formation and implicate SHP2 as a key regulator of chondrocyte specification, organization and maturation.
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影响因子：
8
作者：
Ho, L.;Ali, S. A.;Al-Jazrawe, M.;Kandel, R.;Wunder, J. S.;Alman, B. A.
通讯作者：
Alman, B. A.
影响因子：
2.7
作者：
Ferrari, D;Kosher, RA
通讯作者：
Kosher, RA
DOI：
10.1073/pnas.0910875107
发表时间：
2010-02-02
影响因子：
11.1
作者：
Jones, Kevin B.;Piombo, Virginia;Sheffield, Val C.
通讯作者：
Sheffield, Val C.
软骨细胞中SHP2缺乏症的诱导会导致小鼠的严重脊柱侧弯和脑脊柱。
影响因子：
3
作者：
Kim HK;Aruwajoye O;Sucato D;Richards BS;Feng GS;Chen D;King PD;Kamiya N
通讯作者：
Kamiya N
影响因子：
4.3
作者：
Bauler TJ;Kamiya N;Lapinski PE;Langewisch E;Mishina Y;Wilkinson JE;Feng GS;King PD
通讯作者：
King PD