基于可诱导的条件性敲除ERK1/2的混合性软骨瘤病小鼠模型的构建及病理机制研究

Metachondromatosis (MC) is an autosomal dominant inheritant disease with the characteristics of multiple exostoses and enchondromas. Previous studies have shown that loss of function of PTPN11 causes formation of MC in mouse models and in humans, however the underlying molecular mechanism remains unknown. ERK-MAPK is considered as the key downstream signaling of SHP2 protein encoded by PTPN11 gene. We hypothesize that aberrant ERK-MAPK signaling could cause MC and osteochondroprogenitor cell-specific knockout of ERK1/2 should result in MC. Previously, we demonstrated that the ERK-MAPK signaling pathway inhibits chondrogenesis in a mouse model. Ablation of ERK1/2 expression in mesenchymal cells resulted in a phenotype similar MC, unfortunately mice died 2-3 weeks after birth which hampered further investigation. In this study, we aim to establish a new MC model by using Prx1CreER-GFP transgene mice. The addition of tamoxifen is expected to induce osteochondroprogenitor cell-specific knockout of ERK1/2 without causing premature death in mice. By in vivo and in vitro analysis, we postulate that increased chondrogenesis caused by disruption of ERK1/2 in osteochondroprogenitor cells was most likely the key factor of MC. More importantly, we will also investigate the possibility of treating MC by stimulating Wnt/β-catenin pathway using our new animal model.

混合性软骨瘤病（MC）是一种罕见的常染色体显性遗传病。PTPN11突变可导致MC发生，但PTPN11导致MC的发病机理尚待阐明。ERK-MAPK是PTPN11编码的SHP2蛋白的重要下游通路，我们推测PTPN11缺失导致ERK-MAPK信号紊乱是MC的主要病因，在骨干细胞中敲除ERK1/2亦可导致MC发生。我们前期通过基因敲除小鼠模型证实ERK-MAPK信号通路抑制软骨发生。通过Prx1Cre敲除ERK1/2在间充质细胞表达，小鼠表现为类似MC表型，但出生后2-3周死亡，无法进一步研究。为避免小鼠过早死亡，我们选用Prx1CreER-GFP通过他莫昔芬诱导ERK1/2的敲除，以期建立一种新的MC模型。基于对该MC模型的分析，我们有望证明ERK1/2在骨干细胞的缺失导致软骨发生增加是MC关键病因。另外我们通过氯化锂增强Wnt/β-catenin信号通路来抑制软骨发生，探讨其对MC的治疗作用。

混合性软骨瘤病（MC）是一种罕见的常染色体显性遗传病。本研究基于PTPN11缺失导致ERK-MAPK信号紊乱是MC的主要病因，提出在骨干细胞中敲除ERK1/2亦可导致MC发生的假设。通过转基因技术，选择性敲除ERK1/2在骨干细胞中表达，制 备 出Prx1CreER-GFP，ERK1-/-，ERK2flox/flox基因敲除小鼠，通过体内及体外试验对该小鼠模型的分析，建立罕见病混合性软骨瘤病（MC）的一种新的动物模型，并阐述了ERK1/2在MC发病中的作用，提出MC新的发病机制，并初步探讨了Wnt/β-catenin信号通路来治疗MC的新方法。本研究着眼于基础研究与临床应用的紧密结合，通过建立罕见病混合性软骨瘤病（MC）的新的动物模型，证实 ERK1/2在MC发病机制中的关键作用，根据此致病机理，尝试通过药物上调Wnt/β-catenin 信号通路，达到预防或治疗罕见病MC的作用，从而为临床上治疗MC提供新的思路。

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