Role of TGF-β in a mouse model of high turnover renal osteodystrophy.
Role of TGF-β in a mouse model of high turnover renal osteodystrophy.
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DOI：
10.1002/jbmr.2120
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Schiavi SC
中科院分区：
文献类型：
--
作者：
Liu S;Song W;Boulanger JH;Tang W;Sabbagh Y;Kelley B;Gotschall R;Ryan S;Phillips L;Malley K;Cao X;Xia TH;Zhen G;Cao X;Ling H;Dechow PC;Bellido TM;Ledbetter SR;Schiavi SC
骨转换改变是慢性肾病-矿物质和骨病（CKD-MBD）的一个关键病理特征。 TGF-β1（一种已知的骨转换调节因子）的表达在 CKD 患者的骨活检中增加。同样，jck 小鼠（一种高周转肾性骨营养不良模型）的骨骼中 TGF-β1 mRNA 和下游信号传导增加。使用中和性抗 TGF-β 抗体 (1D11) 来探索 TGF-β 在肾性骨营养不良中的作用。 jck 的 1D11 给药显着减弱血清骨钙素和 I 型胶原 C 端肽的升高。组织形态计量学分析表明，1D11 给药可增加骨体积并以剂量依赖性方式抑制骨转换的升高。这些效应与成骨细胞和破骨细胞表面积的减少有关。 μCT 证实了观察到的骨小梁体积的增加，并证明了小梁结构的改善和皮质厚度的增加。 1D11 给药与成骨细胞标记基因（Runx2、碱性磷酸酶、骨钙素）和破骨细胞标记基因 Trap5 的表达显着降低相关。重要的是，在该模型中，1D11 没有改善肾功能或降低血清 PTH 水平，表明 1D11 对骨骼的影响与肾功能或甲状旁腺功能的变化无关。 1D11 还显着减轻腺嘌呤诱导的尿毒症大鼠模型中的高周转骨病。通过定量免疫印迹分析评估，抗体给药与骨中 pSMAD2/SMAD2 的减少相关，但与骨髓中的 pSMAD2/SMAD2 减少无关。免疫染色显示成骨细胞和骨细胞中存在 pSMAD 染色，但破骨细胞中没有，表明 1D11 对破骨细胞的影响可能是间接的。免疫印迹和全基因组 mRNA 表达分析证实了我们之前的观察结果，即骨中 Wnt/β 连环蛋白表达的抑制与 jck 小鼠和 CKD 患者骨活检中破骨细胞活性的增加相关。此外，我们的数据表明，TGF-β 升高可能部分通过抑制 β-连环蛋白信号传导导致高周转疾病的发病机制。
Altered bone turnover is a key pathologic feature of chronic kidney disease-mineral and bone disorder (CKD-MBD). Expression of TGF-β1, a known regulator of bone turnover, is increased in bone biopsies from individuals with CKD. Similarly, TGF-β1 mRNA and downstream signaling is increased in bones from jck mice, a model of high-turnover renal osteodystropy. A neutralizing anti-TGF-β antibody (1D11) was used to explore TGF-βs role in renal osteodystrophy. 1D11 administration to jck significantly attenuated elevated serum osteocalcin and type I collagen C-telopeptides. Histomorphometric analysis indicated that 1D11 administration increased bone volume and suppressed the elevated bone turnover in a dose-dependent manner. These effects were associated with reductions in osteoblast and osteoclast surface areas. μCT confirmed the observed increase in trabecular bone volume and demonstrated improvements in trabecular architecture and increased cortical thickness. 1D11 administration was associated with significant reductions in expression of osteoblast marker genes (Runx2, alkaline phosphatase, osteocalcin) and the osteoclast marker gene, Trap5. Importantly, in this model, 1D11 did not improve kidney function or reduce serum PTH levels indicating that 1D11 effects on bone are independent of changes in renal or parathyroid function. 1D11 also significantly attenuated high turnover bone disease in the adenine-induced uremic rat model. Antibody administration was associated with a reduction in pSMAD2/SMAD2 in bone but not bone marrow as assessed by quantitative immunoblot analysis. Immunostaining revealed pSMAD staining in osteoblasts and osteocytes but not osteoclasts, suggesting 1D11 effects on osteoclasts may be indirect. Immunoblot and whole genome mRNA expression analysis confirmed our previous observation that repression of Wnt/β catenin expression in bone is correlated with increased osteoclast activity in jck mice and bone biopsies from CKD patients. Furthermore, our data suggests that elevated TGF-β may contribute to the pathogenesis of high turnover disease partially through inhibition of β-catenin signaling.
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影响因子：
6.2
作者：
Jastrzebski, Sandra;Kalinowski, Judith;Stolina, Marina;Mirza, Faryal;Torreggiani, Elena;Kalajzic, Ivo;Won, Hee Yeon;Lee, Sun-Kyeong;Lorenzo, Joseph
通讯作者：
Lorenzo, Joseph
影响因子：
4.2
作者：
Hernandez, MV;Peris, P;MunozGomez, J
通讯作者：
MunozGomez, J
影响因子：
6.2
作者：
Bivi, Nicoletta;Condon, Keith W.;Allen, Matthew R.;Farlow, Nathan;Passeri, Giovanni;Brun, Lucas R.;Rhee, Yumie;Bellido, Teresita;Plotkin, Lilian I.
通讯作者：
Plotkin, Lilian I.
影响因子：
5.6
作者：
Karst, M;Gorny, G;Oursler, MJ
通讯作者：
Oursler, MJ
影响因子：
6.2
作者：
Jilka, RL;Weinstein, RS;Manolagas, SC
通讯作者：
Manolagas, SC