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1.
Monolayer cultures of normal human bone cells contain multiple subpopulations of alkaline phosphatase positive cells 总被引:5,自引:0,他引:5
Toshikatsu Matsuyama K. -H. William Lau Jon E. Wergedal 《Calcified tissue international》1990,47(5):276-283
Summary Cytochemical staining of normal human bone cells in monolayer cultures for alkaline phosphatase (ALP) indicated that the cultures
contained mixed-cell populations. Time course evaluations of the cytochemical staining revealed, in addition to the ALP-negative
cell population, at least two subpopulations of ALP-positive human bone cells with different levels of ALP. A cytochemical
method has been developed which separates the ALP-positive cells into high and intermediate ALP subpopulations. In this method,
human bone cells were stained for ALP using an azo-dye method and incubating at 4°C for 10 and 30 minutes, respectively. We
defined the cell population that stained positively for ALP at 10 minutes as strong ALP-positive cells, and both strong and
intermediate cells were stained at 30 minutes. The intermediate cells were determined from the difference between the values
at the two time points. The intra- and interassay variations of the assay, with the same investigator in blinded investigations,
were both less than 10% and the interobserver variation was approximately 25%. Analysis of the distribution of ALP levels
in cells with a laser densitometer confirmed the presence of at least three cell subpopulations. 1,25(OH)2D3 treatment increased the proportions of both ALP-positive cell populations, whereas TGF-beta treatment increased only the
intermediate ALP-positive cell population. On the contrary, fluoride increased the proportion of the strong ALP cells, and
IGF-1 had no effect on the proportions of either ALP-positive subpopulation. When the ALP-specific activity was compared with
the percentage of each ALP-positive subpopulations for the cells treated with effectors, the ALP-specific activity correlated
with the total ALP-positive and with the strong ALP-positive populations but not with the intermediate ALP-positive subpopulation.
In summary, this study represents the first evidence that normal human bone cells in monolayer cultures contained at least
two subpopulations of ALP-positive cells, and that bone cell effectors could have differential effects on each cell population. 相似文献
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Higashiyama H Yoshimoto D Kaise T Matsubara S Fujiwara M Kikkawa H Asano S Kinoshita M 《Experimental and molecular pathology》2007,83(1):39-46
Activin receptor-like kinase 5 (ALK5) is a type I receptor of transforming growth factor (TGF)-beta. ALK5 inhibition has been reported to attenuate the tissue fibrosis including pulmonary fibrosis, renal fibrosis and liver fibrosis. To elucidate the inhibitory mechanism of ALK5 inhibitor on pulmonary fibrosis in vivo, we performed the histopathological assessment, gene expression analysis of extracellular matrix (ECM) genes and immunohistochemistry including receptor-activated Smads (R-Smads; Smad2/3), CTGF, myofibroblast marker (alpha-smooth muscle actin; aSMA) and type I collagen deposition in the lung using Bleomycin (BLM)-induced pulmonary fibrosis model. ALK5 inhibitor, SB-525334 (10 mg/kg or 30 mg/kg) was orally administered at twice a day. Lungs were isolated 5, 7, 9 and 14 days after BLM treatment. BLM treatment led to significant pulmonary fibrotic changes accompanied by significant upregulation of ECM mRNA expressions, Smad2/3 nuclear translocation, CTGF expression, myofibroblast proliferation and type I collagen deposition. SB-525334 treatment attenuated the histopathological alterations in the lung, and significantly decreased the type I and III procollagen and fibronectin mRNA expression. Immunohistochemistry revealed that SB-525334 treatment showed significant attenuation in Smad2/3 nuclear translocation, decrease in CTGF-expressing cells, myofibroblast proliferation and type I collagen deposition. These results suggest that ALK5 inhibition attenuates R-Smads activation thereby attenuates pulmonary fibrosis. 相似文献
6.
Steven E. Wilson Lycia Pedral Sampaio Thomas Michael Shiju Guilherme S. L. Hilgert Rodrigo Carlos de Oliveira 《Investigative ophthalmology & visual science》2022,63(1)
PurposeTo highlight the cellular, matrix, and hydration changes associated with opacity that occurs in the corneal stroma after injury.MethodsReview of the literature.ResultsThe regulated transition of keratocytes to corneal fibroblasts and myofibroblasts, and of bone marrow-derived fibrocytes to myofibroblasts, is in large part modulated by transforming growth factor beta (TGFβ) entry into the stroma after injury to the epithelial basement membrane (EBM) and/or Descemet''s membrane. The composition, stoichiometry, and organization of the stromal extracellular matrix components and water is altered by corneal fibroblast and myofibroblast production of large amounts of collagen type I and other extracellular matrix components—resulting in varying levels of stromal opacity, depending on the intensity of the healing response. Regeneration of EBM and/or Descemet''s membrane, and stromal cell production of non-EBM collagen type IV, reestablishes control of TGFβ entry and activity, and triggers TGFβ-dependent myofibroblast apoptosis. Eventually, corneal fibroblasts also disappear, and repopulating keratocytes reorganize the disordered extracellular matrix to reestablish transparency.ConclusionsInjuries to the cornea produce varying amounts of corneal opacity depending on the magnitude of cellular and molecular responses to injury. The EBM and Descemet''s membrane are key regulators of stromal cellularity through their modulation of TGFβ. After injury to the cornea, depending on the severity of the insult, and possibly genetic factors, trace opacity to severe scarring fibrosis develops. Stromal cellularity, and the functions of different cell types, are the major determinants of the level of the stromal opacity. 相似文献
7.
Joan Seoane 《Clinical & translational oncology》2008,10(1):14-19
The TGFß pathway has recently emerged as a putative therapeutic target against cancer. However, TGFß has a complex and dual role in cancer. In normal epithelial cells and early tumours, TGFß acts as a tumour suppressor. In contrast, during tumour progression TGFß becomes an oncogenic factor inducing proliferation, angiogenesis, invasion and metastasis, as well as suppressing the anti-tumoral immune response. The role of TGFß in oncogenesis requires the precise understanding of the TGFß pathway in order to design optimal therapeutic approaches and select the patient population that may benefit from an anti-TGFß therapy. Here we review the rationale for evaluating TGFß signalling inhibitors as cancer therapeutics, and the progress made in the preclinical and clinical testing of anti-TGFß compounds. 相似文献
8.
Tu-Anh N. Ha Matthew C. Madison Farrah Kheradmand Kenneth W. Altman 《American journal of otolaryngology》2019,40(1):89-92
Purpose
To build a murine model for tobacco smoke and electronic cigarette vapor exposure to characterize the inflammatory and immune responses in the larynx.Materials and methods
In this pilot study, twenty-four wild-type C57BL/6 mice were divided into four groups: smoke, vapor with nicotine, vapor without nicotine, and air only. Following daily exposure for 4?months, larynges were dissected and processed with cytokine detection arrays. Each laryngeal cytokine level between the four different groups was analyzed statistically by using statistical analysis software (SAS) to calculate the analysis of variance (ANOVA).Results
IL-4 was the only cytokine found to achieve statistically significant different levels in this study, with elevated levels of IL-4 in the tobacco smoke and vapor with nicotine groups compared to the levels found in the vapor without nicotine and air only groups (p?=?0.0418). While statistically non-significant, prominent findings revealed up-regulation of TGF-β2 and TGF-β3 in the smoke group, but near-normal levels of TGF-β2 and TGF-β3 and suppression of IL-10 in the vapor groups (p?>?0.05).Conclusion
The potential utility of the murine model is established for studying the inflammatory and immune effects of tobacco smoke and vapor on the mammalian larynx. IL-4 levels in mice larynges were significantly elevated in the tobacco smoke and vapor with nicotine groups. 相似文献9.
Vuruskan H Caliskan Z Kordan Y Ozakin C Yavascaoglu I Oktay B 《Urological research》2005,33(6):465-469
We measured plasma concentrations of TGF-beta 1 in patients with obstructive ureteral calculi and compared them with the plasma concentrations of healthy volunteers. The present study was a prospective study containing a homogenous group of patients with unilateral ureteral obstruction (UUO). The study consisted of patients with ureteral stones less than 7 mm in diameter that caused mild to moderate obstruction. All patients were referred by the emergency department of our hospital and examined between April 2003 and April 2004. The presence and characteristics of both stone and obstruction were determined by plain abdominal x-ray and gray-scale ultrasonography (US). Blood samples were collected from both patients and control individuals on admission and 1 week after conservative follow-up. The plasma TGF-beta 1 concentration was determined using a quantitative sandwich enzyme immunoassay specific for TGF-beta 1. There were 35 patients with 20 women and 15 men (average age 26.8±5.9 years), and 15 volunteers in the control group, with nine women and six men (average age 24.2±4.5 years). Average stone size was 5.6 mm±1.2 mm (range 3.5–7) for the patient group. US showed the presence of mild hydronephrosis in 24 and moderate hydronephrosis in 11 patients. Plasma concentrations of TGF-beta 1 in patients with ureteral obstruction (1,117±5.8 ng/ml, range 36–2,442 ng/ml) were significantly higher than those in the healthy control group (32±4 ng/ml) on admission (P<0.001). There was a significant increase in TGF-beta 1 plasma concentrations in the patient group (33,525±6.8 ng/ml, range 1,107–73,288 ng/ml) after 1 week follow-up (P<0.001). Ureteral obstruction increases plasma TGF-beta 1 concentrations in patients with ureteral stones as in UUO models in animal studies. A concomitant treatment with an anti-fibrotic agent may reduce the incidence of renal injury during obstruction. 相似文献
10.
Hammerhead ribozyme targeting connective tissue growth factor mRNA blocks transforming growth factor-beta mediated cell proliferation 总被引:4,自引:0,他引:4
PURPOSE: Excessive scarring following trauma or surgery of cornea, conjunctiva or retina can greatly impair visual outcome. At present, no agents are clinically available that selectively reduce activity of genes that regulate fibrosis. Connective tissue growth factor (CTGF) has been linked to fibrosis in several tissues, including cornea and conjunctiva. In this study, hammerhead ribozymes targeting CTGF mRNA were synthesized, kinetic parameters were measured, and the effect on TGF-beta-mediated cell proliferation was measured in cultured human fibroblasts. METHODS: The mRNA sequence of human CTGF was scanned for potential hammerhead ribozyme cleavage sites, and predicted secondary folding structures around the sites were calculated. Synthetic 12mer ribozymes and 33mer oligonucleotide mRNA targets corresponding to two sites were synthesized, and kinetic constants calculated from Hanes-Wolff plots of in vitro cleavage reactions. The ribozyme with higher percentage cleavage and kinetic rate was cloned into an expression plasmid (pTR-UF21) and stably transfected into cultured human fibroblasts. An inactive ribozyme plasmid served as a negative control. The effects of the ribozyme on expression of TGF-beta-induced CTGF mRNA and protein levels were measured using ELISA and real-time TaqMan quantitative RT-PCR. Finally, the effect of the CTGF ribozyme on TGF-beta-mediated proliferation of fibroblasts was measured using a non-radioactive cell proliferation microtiter assay. RESULTS: Of the eight potential hammerhead ribozyme cleavage sites in human CTGF mRNA, two sites (CHR 745, and CHR 859) were identified with optimal secondary folding. CHR 859 cleaved 94% of the target mRNA, compared to 46% cleavage for CHR 745 after 16 hr of reaction. CHR 859 had a K(m) of 1.56 microM and a K(cat) of 2.97 min(-1), while CHR 745 had a K(m) of 7.80 microM and a K(cat) of 5.7 min(-1). The turnover numbers (K(cat)/K(m)) of CHR 859 and CHR 745 were 1.9 x 10(6) M min(-1) and 7.4 x 10(5) M min(-1), respectively, indicating CHR 859 is 2.6 times more efficient than CHR 745 in destroying CTGF mRNA. Stable transfection of CHR 859 into human fibroblasts reduced CTGF mRNA levels 55% and protein levels 72% compared to the inactive ribozyme control. Furthermore, TGF-beta-induced cell proliferation was reduced 90% in fibroblasts stably transfected with CHR 859 compared to control cell groups. CONCLUSIONS: The CHR 859 hammerhead ribozyme cleaved human CTGF mRNA with high kinetic efficiency in vitro, effectively reduced levels of CTGF mRNA and protein in cultured human fibroblasts, and blocked TGF-beta-induced cell proliferation without nonspecific toxicity. These data support the concept that CTGF mediates TGF-beta-induced cell proliferation, and imply that regulating CTGF expression with ribozymes may be effective in reducing ocular scarring. 相似文献