Inhibition of ALK5 signaling induces physeal dysplasia in rats
Inhibition of ALK5 signaling induces physeal dysplasia in rats
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DOI：
10.1080/01926230701198469
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发表时间：
2007-01-01
影响因子：
1.5
通讯作者：
Gellibert, Francoise
中科院分区：
文献类型：
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作者：
Frazier, Kendall;Thomas, Roberta;Gellibert, Francoise
TGF-垂直条β垂直条及其1型（ALK 5）受体对纤维化的发病机制至关重要。在10周龄Sprague-Dawley大鼠中进行的4天或更长时间的毒理学研究中，使用ALK 5抑制剂（GW 788388），观察到股骨骺板肥大和增殖区扩张。存在骨骺下骨质增生、软骨细胞肥大/增生和基质增加。激光显微切割ALK 5受体处理的大鼠和处理3天后处死的对照大鼠的骨骺区。通过实时PCR扩增TGF-垂直条β垂直条1、TGF-垂直条β垂直条2、ALK 5、IHH、VEGF、BMP-7、IGF-1、bFGF和PTHrP的转录本。IGF和IHH增加，在所有生长区与治疗，但最突出的prehypertrophic区。TGF-垂直条β垂直条2、bFGF和BMP 7表达在增生区、前增生区和肥大区中增加。PTHrP在增生区表达升高，而在肥大区表达降低。VEGF表达增加治疗后，在前和肥大区。ALK 5表达在前肥大区升高。酶谱显示明胶分解活性在处理后降低。肥大区的凋亡标志物（TUNEL和caspase-3）减少。通过拓扑异构酶II和Ki 67评估的增殖在多个区域中增加。Movat染色显示蛋白多糖沉积改变。在远高于导致纤维化的剂量时发生骨骺变化。各种因素的相互作用在骨骺发育不良表型的产生中是重要的。
TGF-vertical bar beta vertical bar, and its type 1 (ALK5) receptor, are critical to the pathogenesis of fibrosis. In toxicologic studies of 4 or more days in 10-week-old Sprague-Dawley rats, using an ALK5 inhibitor (GW788388), expansion of hypertrophic and proliferation zones of femoral physes were noted. Subphyseal hyperostosis, chondrocyte hypertrophy/hyperplasia, and increased matrix were present. Physeal zones were laser microdissected from ALK5 inhibitor-treated and control rats sacrificed after 3 days of treatment. Transcripts for TGF-vertical bar beta vertical bar 1, TGF-vertical bar beta vertical bar 2, ALK5, IHH, VEGF, BMP-7, IGF-1, bFGF, and PTHrP were amplified by real-time PCR. IGF and IHH increased in all physis zones with treatment, but were most prominent in prehypertrophic zones. TGF-vertical bar beta vertical bar 2, bFGF and BMP7 expression increased in proliferative, pre- and hypertrophic zones. PTHrP expression was elevated in proliferative zones but decreased in hypertrophic zones. VEGF expression was increased after treatment in pre- and hypertrophic zones. ALK5 expression was elevated in prehypertrophic zones. Zymography demonstrated gelatinolytic activity was reduced after treatment. Apoptotic markers (TUNEL and caspase-3) were decreased in hypertrophic zones. Proliferation assessed by Topoisomerase II and Ki67 was increased in multiple zones. Movat stains demonstrated that proteoglycan deposition was altered. Physeal changes occurred at doses well above those resulting in fibrosis. Interactions of factors is important in producing the physeal dysplasia phenotype.