Dysregulated transforming growth factor beta (TGF-b) signaling is associated with a spectrum of osseous defects as seen in Loeys-Dietz syndrome, Marfan syndrome, and Camurati-Engelmann disease. Intriguingly, neurofibromatosis type 1 (NF1) patients exhibit many of these characteristic skeletal features, including kyphoscoliosis, osteoporosis, tibial dysplasia, and pseudarthrosis; however, the molecular mechanisms mediating these phenotypes remain unclear. Here, we provide genetic and pharmacologic evidence that hyperactive TGFb1 signaling pivotally underpins osseous defects in Nf1 flox/À ;Col2.3Cre mice, a model which closely recapitulates the skeletal abnormalities found in the human disease. Compared to controls, we show that serum TGF-b1 levels are fivefold to sixfold increased both in Nf1 flox/À ;Col2.3Cre mice and in a cohort of NF1 patients. Nf1-deficient osteoblasts, the principal source of TGF-b1 in bone, overexpress TGF-b1 in a gene dosage-dependent fashion. Moreover, Nf1-deficient osteoblasts and osteoclasts are hyperresponsive to TGF-b1 stimulation, potentiating osteoclast bone resorptive activity while inhibiting osteoblast differentiation. These cellular phenotypes are further accompanied by p21-Ras-dependent hyperactivation of the canonical TGF-b1-Smad pathway. Reexpression of the human, fulllength neurofibromin guanosine triphosphatase (GTPase)-activating protein (GAP)-related domain (NF1 GRD) in primary Nf1-deficient osteoblast progenitors, attenuated TGF-b1 expression levels and reduced Smad phosphorylation in response to TGF-b1 stimulation. As an in vivo proof of principle, we demonstrate that administration of the TGF-b receptor 1 (TbRI) kinase inhibitor, SD-208, can rescue bone mass deficits and prevent tibial fracture nonunion in Nf1 flox/À ;Col2.3Cre mice. In sum, these data demonstrate a pivotal role for hyperactive TGF-b1 signaling in the pathogenesis of NF1-associated osteoporosis and pseudarthrosis, thus implicating the TGF-b signaling pathway as a potential therapeutic target in the treatment of NF1 osseous defects that are refractory to current therapies.
See also Binder BR. Thrombin is bad, accepted; but is smoking good to prevent restenosis? This issue, pp 2188-90.Summary. Background: Coagulation proteins promote neointimal hyperplasia and vascular remodelling after vessel injury, but the precise mechanisms by which they act in vivo remain undetermined. Objectives: This study, using an injury model in which the neointima is derived from bone marrow (BM)-derived cells, compared inhibition of tissue factor or thrombin on either BM-derived or existing vascular smooth muscle cells. Methods: Two transgenic (Tg) mouse strains expressing membrane-tethered tissue factor pathway inhibitor (TFPI) or hirudin (Hir) fusion proteins driven by an a smooth muscle actin (SMA) promoter were generated (a-TFPI-Tg and a-Hir-Tg) and the phenotype after wire-induced endovascular injury was compared with that in wild-type (WT) controls. Results: WT mice developed progressive neointimal expansion, whereas injury in either Tg was followed by repair back to a preinjured state. This was also seen when WT mice were reconstituted with BM from Tg mice but not when Tgs were reconstituted with WT BM, in which injury was followed by slowly progressive neointimal expansion. Injection of CD34+ cells from Tg mice into injured WT mice resulted in the accumulation of fusion protein-expressing cells from day 3 onwards and an absence of neointimal hyperplasia in those areas. Conclusions: Neointimal development after wire-induced endovascular injury in mice was completely inhibited when BM-derived cells infiltrating the damaged artery expressed membrane tethered anticoagulant fusion proteins under an a-SMA promoter. These findings enhance our understanding of the pathological role that coagulation proteins play in vascular inflammation.
While nullizygous loss of NF1 leads to myeloid malignancies, haploinsufficient loss of NF1 (Nf1) has been shown to contribute to osteopenia and osteoporosis which occurs in approximately 50 percent of neurofibromatosis type 1 (NF1) patients. Bone marrow mononuclear cells of haploinsufficient NF1 patients and Nf1+/- mice exhibit increased osteoclastogenesis and accelerated bone turnover, however the culprit hematopoietic lineages responsible for perpetuating these osteolytic manifestations have yet to be elucidated. Here we demonstrate that conditional inactivation of a single Nf1 allele within the myeloid progenitor cell population (Nf1-LysM) is necessary and sufficient to promote multiple osteoclast gain-in-functions, resulting in enhanced osteoclastogenesis and accelerated osteoclast bone lytic activity in response to pro-resorptive challenge in vivo. Surprisingly, mice conditionally Nf1 heterozygous in mature, terminally differentiated osteoclasts (Nf1-Ctsk) do not exhibit any of these skeletal phenotypes, indicating a critical requirement for Nf1 haploinsufficiency at a more primitive/progenitor stage of myeloid development in perpetuating osteolytic activity. We further identified p21Ras dependent hyper-phosphorylation of Pu.1 within the nucleus of Nf1 haploinsufficent myelomoncytic osteoclast precursors, providing a novel therapeutic target for the potential treatment of NF1 associated osteolytic manifestations.
Purpose : To analyze the up-regulated genes of poor prognosis in colorectal cancer and gastric cancer by bioinformatics. Methods: We searched the gene expression profiles GSE156355 and GSE64916 in colorectal cancer and gastric cancer tissues in NCBI-GEO. With P value < 0.05 and log2>1 as the standard, Venn diagram software was used to identify the common DEGs in the two data sets. Kaplan Meier plotter was used to analyze the survival rate data of common differentially expressed genes, draw and select survival curves, and analyze their expression levels. Results: A total of 97 genes were detected to be up-regulated in the two gene expression profiles. There were 19 genes in the prognosis of gastric cancer and 15 genes in the prognosis of colorectal cancer that had significant differences in the survival rate. Among them, KCNQ1, TRIM29, GART, MSX1, SNAI1, SUV39H2, LOXL2 and KCTD14 significantly decreased the survival rate of gastric cancer and colorectal cancer. The expression of MSX1 was the highest in gastric cancer. The expression level of KCTD14 was the highest in colorectal cancer, and there was no significant difference in the expression levels of other genes. Conclusion: There are 19 and 15 genes with significantly different prognostic viability in gastric cancer and colorectal cancer, respectively. The survival rates of KCNQ1, TRIM29, GART, Msx1, SNAI1, SUV39H2, LOXL2 and KCTD14 were significantly decreased in gastric cancer and colorectal cancer. The expression of MSX1 was the highest in gastric cancer. The expression of KCTD14 was the highest in colorectal cancer.
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