Role of TGF-β in a Mouse Model of High Turnover Renal Osteodystrophy

肾性骨营养不良 骨重建 内分泌学 内科学 转化生长因子 医学 肾脏疾病
作者
Shiguang Liu,Wenping Song,Joseph Boulanger,Wen Tang,Yves Sabbagh,Brian P. Kelley,Russell Gotschall,Susan Ryan,Lucy Phillips,Katie Malley,Xiaohong Cao,Tai-He Xia,Gehua Zhen,Xu Cao,Hong Ling,Paul C. Dechow,Teresita Bellido,Steven Ledbetter,Susan C. Schiavi
出处
期刊:Journal of Bone and Mineral Research [Wiley]
卷期号:29 (5): 1141-1157 被引量:30
标识
DOI:10.1002/jbmr.2120
摘要

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 osteodystrophy. A neutralizing anti-TGF-β antibody (1D11) was used to explore TGF-β's 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. Micro-computed tomography (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 parathyroid hormone (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 suggest that elevated TGF-β may contribute to the pathogenesis of high-turnover disease partially through inhibition of β-catenin signaling.
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