Disturbed osteoblastic differentiation of fibrous hamartoma cell from congenital pseudarthrosis of the tibia associated with neurofibromatosis type I.
Disturbed osteoblastic differentiation of fibrous hamartoma cell from congenital pseudarthrosis of the tibia associated with neurofibromatosis type I.
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DOI：
10.4055/cios.2011.3.3.230
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发表时间：
2011-09
影响因子：
2.5
通讯作者：
Choi IH
中科院分区：
文献类型：
--
作者：
Lee DY;Cho TJ;Lee HR;Lee K;Moon HJ;Park MS;Yoo WJ;Chung CY;Choi IH
纤维错构瘤是先天性胫骨假关节（CPT）的关键病理，它具有低成骨性和高破骨细胞性。本研究进一步探讨了纤维错构瘤细胞成骨分化障碍的机制。成纤维细胞样细胞从11例CPT伴I型神经纤维瘤病（NF 1）患者的酶解纤维错构瘤中获得。取3例未加CPT或NF 1的患者胫骨远端骨膜作为对照。使用逆转录酶PCR（RT-PCR）测定Wnt配体及其典型受体（如Lrp 5和β-连环蛋白）的mRNA水平。采用定量真实的时间RT-PCR检测rhBMP 2对成骨细胞标志基因mRNA表达的影响。用实时荧光定量RT-PCR检测rhBMP 2处理后成骨细胞分化相关转录因子mRNA表达的变化。Wnt 1和Wnt 3a mRNA在纤维错构瘤中的表达低于胫骨骨膜细胞，但其经典受体无显著性差异。成骨细胞标志物基因表达对rhBMP 2治疗的反应显示出患者间的差异。Col 1a 1 mRNA在大多数纤维性错构瘤组织中表达上调，骨钙素在少数患者中表达上调，ALP在大多数纤维性错构瘤组织中表达下调。响应rhBMP 2的转录因子的mRNA表达的变化也显示了因子间和患者间的变异性。在所有测试的纤维性错构瘤组织中，Dlx 5通过rhBMP 2处理一致上调。在大多数情况下，Msx 2表达下调rhBMP 2，但程度低于对照组织。18例纤维错构瘤组织中有8例Runx 2表达上调。Osterix在2例纤维错构瘤组织中表达上调，3例表达下调。先天性胫骨假关节似乎是由Nf 1单倍不足骨膜细胞异常生长引起的纤维性错构瘤引起的，Nf 1单倍不足骨膜细胞在终末成骨细胞分化中失败，并在该过程的某个阶段被阻止。CPT的这种病理机制应成为开发新型治疗性生物干预的目标。
Fibrous hamartoma is the key pathology of congenital pseudarthrosis of the tibia (CPT), which was shown to have low osteogenicity and high osteoclastogenicity. This study further investigated the mechanism of impaired osteoblastic differentiation of fibrous hamartoma cells. Fibroblast-like cells were obtained from enzymatically dissociated fibrous hamartomas of 11 patients with CPT associated with neurofibromatosis type I (NF1). Periosteal cells were also obtained from the distal tibial periosteum of 3 patients without CPT or NF1 as control. The mRNA levels of Wnt ligands and their canonical receptors, such as Lrp5 and β-catenin, were assayed using reverse transcriptase PCR (RT-PCR). Changes in mRNA expression of osteoblast marker genes by rhBMP2 treatment were assayed using quantitative real time RT-PCR. Changes in mRNA expression of transcription factors specifically involved in osteoblastic differentiation by rhBMP2 treatment was also assayed using quantitative real-time RT-PCR. Wnt1 and Wnt3a mRNA expression was lower in fibrous hamartoma than in tibial periosteal cells, but their canonical receptors did not show significant difference. Response of osteoblastic marker gene expression to rhBMP2 treatment showed patient-to-patient variability. Col1a1 mRNA expression was up-regulated in most fibrous hamartoma tissues, osteocalcin was up-regulated in a small number of patients, and ALP expression was down-regulated in most fibrous hamartoma tissues. Changes in mRNA expression of the transcription factors in response to rhBMP2 also showed factor-to-factor and patient-to-patient variability. Dlx5 was consistently up-regulated by rhBMP2 treatment in all fibrous hamartoma tissues tested. Msx2 expression was down-regulated by rhBMP2 in most cases but by lesser extent than control tissue. Runx2 expression was up-regulated in 8 out of 18 fibrous hamartoma tissues tested. Osterix expression was up-regulated in 2 and down-regulated in 3 fibrous hamartoma tissues. Congenital pseudarthrosis of the tibia appears to be caused by fibrous hamartoma originating from aberrant growth of Nf1 haploinsufficient periosteal cells, which failed in terminal osteoblastic differentiation and arrested at a certain stage of this process. This pathomechanism of CPT should be targeted in the development of novel therapeutic biologic intervention.