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Neurofibromatosis type 1 (NF1) is an autosomal dominant disease caused by mutations in NF1. Among the earliest manifestations is tibial pseudoarthrosis and persistent nonunion after fracture. To further understand the pathogenesis of pseudoarthrosis and the underlying bone remodeling defect, pseudoarthrosis tissue and cells cultured from surgically resected pseudoarthrosis tissue from NF1 individuals were analyzed using whole-exome and whole-transcriptome sequencing as well as genomewide microarray analysis. Genomewide analysis identified multiple genetic mechanisms resulting in somatic biallelic NF1 inactivation; no other genes with recurring somatic mutations were identified. Gene expression profiling identified dysregulated pathways associated with neurofibromin deficiency, including phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways. Unlike aggressive NF1-associated malignancies, tibial pseudoarthrosis tissue does not harbor a high frequency of somatic mutations in oncogenes or other tumor-suppressor genes, such as p53. However, gene expression profiling indicates that pseudoarthrosis tissue has a tumor-promoting transcriptional pattern, despite lacking tumorigenic somatic mutations. Significant overexpression of specific cancer-associated genes in pseudoarthrosis highlights a potential for receptor tyrosine kinase inhibitors to target neurofibromin-deficient pseudoarthrosis and promote proper bone remodeling and fracture healing., (© 2014 American Society for Bone and Mineral Research.)

Objective: The aim of this experimental study was to determine the effects of adjunctive hyperbaric oxygen therapy (HBO) on atrophic tibial nonunion treatment using Ilizarov external fixator., Methods: Twenty New Zealand white rabbits were randomly divided into two equal groups. A circular external fixator was applied to the right tibia of all the rabbits. A 5-mm bone block was resected and a tibial pseudarthrosis was obtained after a 6-month waiting period. The experimental group rabbits (n=10) underwent daily 2.5 ATA HBO therapy for 2 hours for 20 days and the control group rabbits (n=10) did not receive any corresponding treatment. Osteoblastic activity was evaluated with bone scintigraphy on days 30 and 90. Fracture healing was evaluated by plain radiographs on days 30 and 90., Results: On Day 30, radiological scores were statistically similar in both groups (p=0.167). However, on Day 90, the experimental group displayed significantly higher radiological scores (p<0.001). Osteoblastic activity was also higher in the experimental group on both scintigraphic assessments (p=0.005 and p=0.001)., Conclusion: The results of this study suggest that HBO can be used as a supplementary therapy in the management of atrophic tibial nonunion.

Background: Fibrous hamartoma is a key pathologic component of congenital pseudarthrosis of the tibia, a challenging and disabling bone disorder. We investigated the biologic characteristics of fibrous hamartoma cells in order to better understand the pathogenesis of this rare disease., Methods: Fibrous hamartoma tissues were surgically excised at the time of osteosynthesis from seven patients with congenital pseudarthrosis of the tibia associated with neurofibromatosis type 1. Distal tibial periosteum was also harvested as control tissue during tibial derotation osteotomy from two other patients with cerebral palsy and one patient with idiopathic internal tibial torsion. Fibroblast-like cells were enzymatically dissociated and cultured from these tissues. Immunophenotypes were investigated for positive (CD44 and CD105) and negative (CD45 and CD14) mesenchymal lineage cell markers, and the mRNA expressions of bone morphogenetic protein(BMP)-2, BMP-4, and their receptors were assayed by reverse transcription-polymerase chain reaction. After rhBMP-2 treatment, the changes in alkaline phosphatase activity, and in the mRNA expressions of type-I collagen (COL1A1), alkaline phosphatase, and osteocalcin genes, were assayed with use of an RNase protection assay. The mRNA expressions of receptor activator of nuclear factor-kappa B ligand (RANKL) and osteoprotegerin (OPG) were quantitatively assayed with use of real-time RT-PCR. Osteoclastic differentiation of RAW(264.7) cells in coculture with fibrous hamartoma cells was evaluated., Results: All fibrous hamartoma and tibial periosteal cells tested were CD44+/CD105+/CD45-/CD14- and expressed the mRNAs of BMP-2, BMP-4, and their receptors. The baseline mRNA expressions of COL1A1, alkaline phosphatase, and osteocalcin genes in the fibrous hamartoma cells were diverse. These gene expressions were upregulated by BMP treatment in tibial periosteal cells but did not change or were downregulated in fibrous hamartoma cells. Fibrous hamartoma cells expressed higher levels of RANKL and lower levels of OPG than did tibial periosteal cells. Coculture with fibrous hamartoma cells enhanced osteoclastic differentiation of RAW(264.7) cells., Conclusions: Fibrous hamartoma cells maintain some of the mesenchymal lineage cell phenotypes, but do not undergo osteoblastic differentiation in response to BMP. They are more osteoclastogenic than are tibial periosteal cells.

Objective: To investigate the etiology and pathology of congenital pseudarthrosis., Method: Sixty-three specimens were taken from 21 CPT patients. The antibodies, which were used for immunohistochemical studies, were produced against (1) NF-200 or S-100 protein; (2) type I or III collagen; (3) PCNA. The control specimens were taken from neurofibromatosis and traumatic pseudarthrosis. SABC staining was performed., Result: Low positive expression of NF-200 (3.2%) and S-100 (4.8%) was noted in the CPT lesion, whereas high expression of NF-200 (85.2%) and S-100 (88.9%) in the lesion of neurofibromatosis. The soft tissues in CPT had a higher ratio of type III to I collagens in comparison with traumatic pseudarthrosis. Positive expression of PCNA (95.2%) was significantly higher in the soft tissues than that (2.5%) in traumatic pseudarthrosis., Conclusion: CPT is a disease of non-neuro origin. Its occurrence has no direct relation with neurofibromatosis. CPT has its characteristic pathology in the periosteum rather than in the bone. The pathological fracture or non-union of CPT is caused by fibromatosis, which has a strong activity of cellular proliferation and corrosion. CPT has its pathological property similar to a tumor.