title: Role of TGF-β in a mouse model of high turnover renal osteodystrophy.
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.
authors.affiliation: Genzyme, Sanofi-Genzyme R&D Center, Framingham, MA, USA.
authors.forename: Shiguang
authors.initials: S
authors.lastname: Liu
authors.forename: Wenping
authors.initials: W
authors.lastname: Song
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Boulanger
authors.forename: Wen
authors.initials: W
authors.lastname: Tang
authors.forename: Yves
authors.initials: Y
authors.lastname: Sabbagh
authors.forename: Brian
authors.initials: B
authors.lastname: Kelley
authors.forename: Russell
authors.initials: R
authors.lastname: Gotschall
authors.forename: Susan
authors.initials: S
authors.lastname: Ryan
authors.forename: Lucy
authors.initials: L
authors.lastname: Phillips
authors.forename: Katie
authors.initials: K
authors.lastname: Malley
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Cao
authors.forename: Tai-He
authors.initials: TH
authors.lastname: Xia
authors.forename: Gehua
authors.initials: G
authors.lastname: Zhen
authors.forename: Xu
authors.initials: X
authors.lastname: Cao
authors.forename: Hong
authors.initials: H
authors.lastname: Ling
authors.forename: Paul C
authors.initials: PC
authors.lastname: Dechow
authors.forename: Teresita M
authors.initials: TM
authors.lastname: Bellido
authors.forename: Steven R
authors.initials: SR
authors.lastname: Ledbetter
authors.forename: Susan C
authors.initials: SC
authors.lastname: Schiavi
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000943:Antigens, Differentiation / Q000378:metabolism; D012080:Chronic Kidney Disease-Mineral and Bone Disorder / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D024042:Collagen Type I; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D015675:Osteocalcin / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D010455:Peptides; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D055114:X-Ray Microtomography
chemical_list: D057134:Antibodies, Neutralizing; D000943:Antigens, Differentiation; D024042:Collagen Type I; D010455:Peptides; D012333:RNA, Messenger; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; C052929:collagen type I trimeric cross-linked peptide; D015675:Osteocalcin
keywords: BONE TURNOVER; CHRONIC KIDNEY DISEASE; RENAL OSTEODYSTROPHY; TGF-β