Abstract：
Congenital pseudarthrosis of the tibia (CPT) is a severe pathology marked by spontaneous bone fractures that fail to heal, leading to fibrous nonunion. Half of patients with CPT are affected by the multisystemic genetic disorder neurofibromatosis type 1 (NF1) caused by mutations in the NF1 tumor suppressor gene, a negative regulator of RAS-mitogen-activated protein kinase (MAPK) signaling pathway. Here, we analyzed patients with CPT and Prss56-Nf1 knockout mice to elucidate the pathogenic mechanisms of CPT-related fibrous nonunion and explored a pharmacological approach to treat CPT. We identified NF1-deficient Schwann cells and skeletal stem/progenitor cells (SSPCs) in pathological periosteum as affected cell types driving fibrosis. Whereas NF1-deficient SSPCs adopted a fibrotic fate, NF1-deficient Schwann cells produced critical paracrine factors including transforming growth factor-β and induced fibrotic differentiation of wild-type SSPCs. To counteract the elevated RAS-MAPK signaling in both NF1-deficient Schwann cells and SSPCs, we used MAPK kinase (MEK) and Src homology 2 containing protein tyrosine phosphatase 2 (SHP2) inhibitors. Combined MEK-SHP2 inhibition in vivo prevented fibrous nonunion in the Prss56-Nf1 knockout mouse model, providing a promising therapeutic strategy for the treatment of fibrous nonunion in CPT.
摘要：
先天性胫骨假关节（CPT）是一种严重的病理特征是自发性骨折无法愈合，导致纤维状骨不连。一半的CPT患者受到NF1肿瘤抑制基因突变引起的多系统遗传性疾病1型神经纤维瘤病（NF1）的影响，RAS-丝裂原活化蛋白激酶（MAPK）信号通路的负调节因子。这里,我们分析了CPT和Prss56-Nf1基因敲除小鼠的患者,以阐明CPT相关的纤维骨不连的致病机制,并探索了治疗CPT的药理学方法.我们确定了病理性骨膜中NF1缺陷的雪旺氏细胞和骨骼干/祖细胞（SSPC）为驱动纤维化的受影响细胞类型。而缺乏NF1的SSPC采用了纤维化的命运，NF1缺陷的雪旺氏细胞产生关键的旁分泌因子，包括转化生长因子-β，并诱导野生型SSPC的纤维化分化。为了抵消NF1缺陷的施万细胞和SSPC中RAS-MAPK信号传导的升高，我们使用MAPK激酶(MEK)和Src同源2含蛋白酪氨酸磷酸酶2(SHP2)抑制剂。在Prss56-Nf1基因敲除小鼠模型中，体内联合抑制MEK-SHP2可预防纤维骨不连，为CPT中骨不愈合的治疗提供了一种有前途的治疗策略。
