Role of TGF-β in a mouse model of high turnover renal osteodystrophy

Shiguang Liu, Wenping Song, Joseph H. Boulanger, Wen Tang, Yves Sabbagh, Brian Kelley, Russell Gotschall, Susan Ryan, Lucy Phillips, Katie Malley, Xiaohong Cao, Tai He Xia, Gehua Zhen, Xu Cao, Hong Ling, Paul C. Dechow, Teresita M. Bellido, Steven R. Ledbetter, Susan C. Schiavi

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1141-1157
Number of pages17
JournalJournal of Bone and Mineral Research
Volume29
Issue number5
DOIs
StatePublished - 2014

Fingerprint

Chronic Kidney Disease-Mineral and Bone Disorder
Osteoclasts
Bone and Bones
Bone Remodeling
Osteoblasts
Catenins
Osteocalcin
Kidney
Biopsy
Osteocytes
Messenger RNA
Bone Diseases
Adenine
Collagen Type I
Neutralizing Antibodies
Parathyroid Hormone
Serum
Genes
Alkaline Phosphatase
Anti-Idiotypic Antibodies

Keywords

  • bone turnover
  • chronic kidney disease
  • renal osteodystrophy
  • TGF-β

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine
  • Medicine(all)

Cite this

Liu, S., Song, W., Boulanger, J. H., Tang, W., Sabbagh, Y., Kelley, B., ... Schiavi, S. C. (2014). Role of TGF-β in a mouse model of high turnover renal osteodystrophy. Journal of Bone and Mineral Research, 29(5), 1141-1157. https://doi.org/10.1002/jbmr.2120

Role of TGF-β in a mouse model of high turnover renal osteodystrophy. / Liu, Shiguang; Song, Wenping; Boulanger, Joseph H.; Tang, Wen; Sabbagh, Yves; Kelley, Brian; Gotschall, Russell; Ryan, Susan; Phillips, Lucy; Malley, Katie; Cao, Xiaohong; Xia, Tai He; Zhen, Gehua; Cao, Xu; Ling, Hong; Dechow, Paul C.; Bellido, Teresita M.; Ledbetter, Steven R.; Schiavi, Susan C.

In: Journal of Bone and Mineral Research, Vol. 29, No. 5, 2014, p. 1141-1157.

Research output: Contribution to journalArticle

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 2014, 'Role of TGF-β in a mouse model of high turnover renal osteodystrophy', Journal of Bone and Mineral Research, vol. 29, no. 5, pp. 1141-1157. https://doi.org/10.1002/jbmr.2120
Liu, Shiguang ; Song, Wenping ; Boulanger, Joseph H. ; Tang, Wen ; Sabbagh, Yves ; Kelley, Brian ; Gotschall, Russell ; Ryan, Susan ; Phillips, Lucy ; Malley, Katie ; Cao, Xiaohong ; Xia, Tai He ; Zhen, Gehua ; Cao, Xu ; Ling, Hong ; Dechow, Paul C. ; Bellido, Teresita M. ; Ledbetter, Steven R. ; Schiavi, Susan C. / Role of TGF-β in a mouse model of high turnover renal osteodystrophy. In: Journal of Bone and Mineral Research. 2014 ; Vol. 29, No. 5. pp. 1141-1157.
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