日前,，來(lái)自布朗大學(xué)阿爾珀特醫(yī)學(xué)院與羅德島醫(yī)院（Rhode Island ）的研究人員發(fā)現(xiàn),，小鼠體內(nèi)一些特殊軟骨細(xì)胞缺失 Shp-2 酶,，可導(dǎo)致多發(fā)性良性軟骨腫瘤形成,。這一小鼠模型重演了人類一種罕見(jiàn)的腫瘤綜合征：混合性軟骨瘤?。╩etachondromatosis）,。相關(guān)研究論文刊登在了近期出版的《自然》（Nature）雜志上,。
Shp2 酶可在細(xì)胞中調(diào)控其他蛋白質(zhì)和信號(hào)通路的活性。缺失 Shp2 的小鼠會(huì)形成兩種類型的腫瘤：內(nèi)生軟骨瘤（enchondromas）和骨軟骨瘤（osteochondroma）,，此外小鼠還出現(xiàn)了關(guān)節(jié)畸形,。
研究人員表示，轉(zhuǎn)基因人類疾病小鼠模型為了解疾病進(jìn)程以及測(cè)試新療法提供了強(qiáng)大的工具,。在人體內(nèi),，其中的一些良性腫瘤會(huì)進(jìn)展為稱作軟骨肉瘤（chondrosarcomas）的惡性軟骨瘤，由于后者能夠擴(kuò)散傳播其病情更為嚴(yán)重,，甚至可以致命,。
研究人員指出，由于每種細(xì)胞類型都有自身的弱點(diǎn),，了解腫瘤形成的起源細(xì)胞可以幫助開(kāi)發(fā)出新治療,。這項(xiàng)研究發(fā)現(xiàn)了一種新型的軟骨干/祖細(xì)胞群，它們是在骨骼中發(fā)現(xiàn)的第一類癌癥干細(xì)胞,。研究證實(shí)這些細(xì)胞是小鼠模型中腫瘤的起源細(xì)胞,，由此確定了這一罕見(jiàn)疾病的一種潛在療法。在未來(lái),，該模型還可用于為某些形式的軟骨肉瘤開(kāi)發(fā)出新療法,。
一直以來(lái)人們都猜測(cè)軟骨生長(zhǎng)板（Growth Plate）損傷是骨軟骨瘤的形成原因。骨軟骨瘤看起來(lái)就像是軟骨生長(zhǎng)板按錯(cuò)誤的方向脫出生長(zhǎng)而形成,。新研究表明,，骨軟骨瘤的一個(gè)病因是，由于靠近生長(zhǎng)板的一小群細(xì)胞中的酶出現(xiàn)分子異常,，導(dǎo)致了骨骼生長(zhǎng)出大的腫瘤,。這些腫瘤在兒童非常常見(jiàn),。
研究人員總結(jié)道,，這些研究發(fā)現(xiàn)使得科學(xué)家更進(jìn)一步地了解了這些腫瘤的形成機(jī)制。研究人員計(jì)劃下一步開(kāi)發(fā)出一種方法在疾病早期階段阻止腫瘤的生長(zhǎng),，使得無(wú)需用手術(shù)切除它們,。（生物谷Bioon.com）
生物谷推薦英文摘要：
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.
