PTHrP regulates the rate of chondrocyte differentiation during endochondral bone formation. The expression of PTHrP and its regulation by TGF-beta, BMP-2, and PTHrP was examined in upper sternal chondrocytes following 1, 3, and 5 days of continuous treatment. While TGF-beta stimulated the expression of PTHrP (5-fold), PTHrP caused a slight inhibition, and BMP-2 markedly inhibited PTHrP mRNA expression. The effect of these factors on PTHrP expression was not simply related to the maturational state of the cells, since BMP-2 increased, while both PTHrP and TGF-beta decreased the expression of type X collagen. TGF-beta isoforms 1, 2, and 3 all stimulated PTHrP expression. Signaling events involved in the induction of PTHrP by TGF-beta were further evaluated in a PTHrP-promoter CAT construct. The effect of TGF-beta, BMP-2, and PTHrP on the PTHrP-promoter paralleled their effects on mRNA expression, with TGF-beta significantly increasing CAT activity, BMP-2 decreasing CAT activity, and PTHrP having a minimal effect. Co-transfection of the TGF-beta signaling molecule, Smad 3, mimicked the effect of TGF-beta (induction of PTHrP promoter), while dominant negative Smad 3 inhibited the induction of the PTHrP promoter by TGF-beta. Furthermore, infection with a Smad 3-expressing retrovirus mimicked the effects of exogenously added TGF-beta, and induced PTHrP mRNA expression in the infected chondrocyte culture. In contrast, a dominant negative Smad 3 completely inhibited PTHrP promoter stimulation by TGF-beta, but only partially blocked the effect of TGF-beta on PTHrP mRNA synthesis. These findings demonstrate that PTHrP is expressed in chondrocytes undergoing endochondral ossification, and show regulation, at least in part, by TGF-beta through Smad mediated signaling events.

译文

PTHrP调节软骨内骨形成过程中软骨细胞分化的速率。连续治疗1、3和5天后,在上胸骨软骨细胞中检查了PTHrP的表达及其对TGF-β,BMP-2和PTHrP的调节。虽然TGF-β 刺激了PTHrP的表达 (5倍),但PTHrP引起了轻微的抑制,并且BMP-2明显抑制了PTHrP mRNA的表达。这些因素对PTHrP表达的影响不仅与细胞的成熟状态有关,因为BMP-2增加,而PTHrP和TGF-β 均降低了x型胶原的表达。TGF-β 亚型1、2和3均刺激PTHrP表达。在PTHrP启动子CAT构建体中进一步评估了TGF-β 诱导PTHrP所涉及的信号事件。TGF-β,BMP-2和PTHrP对PTHrP启动子的作用与它们对mRNA表达的作用平行,TGF-β 显着增加CAT活性,BMP-2降低CAT活性,而PTHrP的作用最小。TGF-β 信号分子Smad 3的共转染模仿了TGF-β (PTHrP启动子的诱导) 的作用,而显性负Smad 3抑制了TGF-β 对PTHrP启动子的诱导。此外,用表达Smad 3的逆转录病毒感染模仿了外源添加TGF-β 的作用,并在感染的软骨细胞培养物中诱导了PTHrP mRNA的表达。相反,显性阴性Smad 3完全抑制了TGF-β 对PTHrP启动子的刺激,但仅部分阻断了TGF-β 对PTHrP mRNA合成的作用。这些发现表明PTHrP在经历软骨内骨化的软骨细胞中表达,并且至少部分地通过Smad介导的信号事件显示出TGF-β 的调节。

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