Carlier A, Brems H, Ashbourn J M A, Nica I, Legius E, Geris L
Biomechanics Section, KU Leuven, Celestijnenlaan 300 C, PB 2419, 3000 Leuven, Belgium.
Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, O&N 1, Herestraat 49, PB 813, 3000 Leuven, Belgium.
Sci Rep. 2016 Jan 29;7:20010. doi: 10.1038/srep20010.
Congenital pseudarthrosis of the tibia (CPT) is a rare disease which normally presents itself during early childhood by anterolateral bowing of the tibia and spontaneous tibial fractures. Although the exact etiology of CPT is highly debated, 40-80% of CPT patients are carriers of a mutation in the Neurofibromatosis Type 1 (NF1) gene, which can potentially result in an altered phenotype of the skeletal cells and impaired bone healing. In this study we use a computational model of bone regeneration to examine the effect of the Nf1 mutation on bone fracture healing by altering the parameter values of eight key factors which describe the aberrant cellular behaviour of Nf1 haploinsufficient and Nf1 bi-allelically inactivated cells. We show that the computational model is able to predict the formation of a hamartoma as well as a wide variety of CPT phenotypes through different combinations of altered parameter values. A sensitivity analysis by "Design of Experiments" identified the impaired endochondral ossification process and increased infiltration of fibroblastic cells as key contributors to the degree of severity of CPT. Hence, the computational model results have added credibility to the experimental hypothesis of a genetic cause (i.e. Nf1 mutation) for CPT.
先天性胫骨假关节（CPT）是一种罕见疾病，通常在儿童早期表现为胫骨前外侧弯曲和自发性胫骨骨折。尽管CPT的确切病因备受争议，但40%-80%的CPT患者是1型神经纤维瘤病（NF1）基因突变的携带者，这可能会导致骨骼细胞表型改变以及骨愈合受损。在本研究中，我们使用骨再生计算模型，通过改变八个关键因素的参数值来研究Nf1突变对骨折愈合的影响，这八个关键因素描述了Nf1单倍体不足和Nf1双等位基因失活细胞的异常细胞行为。我们表明，该计算模型能够通过不同的参数值改变组合预测错构瘤的形成以及多种CPT表型。通过“实验设计”进行的敏感性分析确定，软骨内骨化过程受损和成纤维细胞浸润增加是CPT严重程度的关键因素。因此，计算模型结果为CPT的遗传病因（即Nf1突变）的实验假设增添了可信度。
