日前，来自布朗大学阿尔珀特医学院与罗德岛医院（Rhode Island ）的研究人员发现，小鼠体内一些特殊软骨细胞缺失 Shp-2 酶，可导致多发性良性软骨肿瘤形成。这一小鼠模型重演了人类一种罕见的肿瘤综合征：混合性软骨瘤病（metachondromatosis）。相关研究论文刊登在了近期出版的《自然》（Nature）杂志上。
Shp2 酶可在细胞中调控其他蛋白质和信号通路的活性。缺失 Shp2 的小鼠会形成两种类型的肿瘤：内生软骨瘤（enchondromas）和骨软骨瘤（osteochondroma），此外小鼠还出现了关节畸形。
研究人员表示，转基因人类疾病小鼠模型为了解疾病进程以及测试新疗法提供了强大的工具。在人体内，其中的一些良性肿瘤会进展为称作软骨肉瘤（chondrosarcomas）的恶性软骨瘤，由于后者能够扩散传播其病情更为严重，甚至可以致命。
研究人员指出，由于每种细胞类型都有自身的弱点，了解肿瘤形成的起源细胞可以帮助开发出新治疗。这项研究发现了一种新型的软骨干/祖细胞群，它们是在骨骼中发现的第一类癌症干细胞。研究证实这些细胞是小鼠模型中肿瘤的起源细胞，由此确定了这一罕见疾病的一种潜在疗法。在未来，该模型还可用于为某些形式的软骨肉瘤开发出新疗法。
一直以来人们都猜测软骨生长板（Growth Plate）损伤是骨软骨瘤的形成原因。骨软骨瘤看起来就像是软骨生长板按错误的方向脱出生长而形成。新研究表明，骨软骨瘤的一个病因是，由于靠近生长板的一小群细胞中的酶出现分子异常，导致了骨骼生长出大的肿瘤。这些肿瘤在儿童非常常见。
研究人员总结道，这些研究发现使得科学家更进一步地了解了这些肿瘤的形成机制。研究人员计划下一步开发出一种方法在疾病早期阶段阻止肿瘤的生长，使得无需用手术切除它们。（生物谷Bioon.com）
生物谷推荐英文摘要：
Nature doi:10.1038/nature12396
Ptpn11 deletion in a novel progenitor causes metachondromatosis by inducing hedgehog signalling
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
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 PTPN11 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 (Ptpn11fl) 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;Ptpn11fl/fl mice had mild osteopetrosis. Notably, however, CtskCre;Ptpn11fl/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;Ptpn11fl/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.
