Inhibition of TGF‐β signaling by 1D11 antibody treatment increases bone mass and quality in vivo

Transforming growth factor β (TGF‐β) is an abundant bone matrix protein that influences osteoblast and osteoclast interactions to control bone remodeling. As such, TGF‐β represents an obvious pharmacologic target with the potential to regulate both bone formation and resorption to improve bone volum...

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Published in:Journal of bone and mineral research 2010-11, Vol.25 (11), p.2419-2426
Main Authors: Edwards, James R, Nyman, Jeffry S, Lwin, Seint T, Moore, Megan M, Esparza, Javier, O'Quinn, Elizabeth C, Hart, Andrew J, Biswas, Swati, Patil, Chetan A, Lonning, Scott, Mahadevan‐Jansen, Anita, Mundy, Gregory R
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Language:English
Subjects:
Animals
Antibodies - pharmacology
Biomechanical Phenomena - drug effects
biomechanics
Bone and Bones - drug effects
Bone and Bones - pathology
bone histomorphometry
Male
Mice
Mice, Inbred C57BL
Organ Size - drug effects
raman microspectroscopy
Signal Transduction - drug effects
TGF‐β
Transforming Growth Factor beta - immunology
Transforming Growth Factor beta - metabolism
treatments: novel entities
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creator Edwards, James R
Nyman, Jeffry S
Lwin, Seint T
Moore, Megan M
Esparza, Javier
O'Quinn, Elizabeth C
Hart, Andrew J
Biswas, Swati
Patil, Chetan A
Lonning, Scott
Mahadevan‐Jansen, Anita
Mundy, Gregory R
description Transforming growth factor β (TGF‐β) is an abundant bone matrix protein that influences osteoblast and osteoclast interactions to control bone remodeling. As such, TGF‐β represents an obvious pharmacologic target with the potential to regulate both bone formation and resorption to improve bone volume and strength. To investigate the skeletal effect of TGF‐β inhibition in vivo, we used an antibody (1D11) specifically directed at all three isoforms of TGF‐β. Normal mice were treated with 1D11 or control antibody (4 weeks), and cortical and trabecular bone was assessed by micro–computed tomographic (µCT) scanning. Bone volume and cellular distribution were determined by histomorphometric analysis of vertebrae and long bones. Also, whole‐bone strength was assessed biomechanically by three‐point bend testing, and tissue‐level modulus and composition were analyzed by nanoindentation and Raman microspectroscopy, respectively. TGF‐β blockade by 1D11 increased bone mineral density (BMD), trabecular thickness, and bone volume by up to 54%, accompanied by elevated osteoblast numbers and decreased osteoclasts. Biomechanical properties of bone also were enhanced significantly by 1D11 treatment, with increased bending strength and tissue‐level modulus. In addition, Raman microspectroscopy demonstrated that 1D11‐mediated TGF‐β inhibition in the bone environment led to an 11% increase in the mineral‐to‐collagen ratio of trabecular bone. Together these studies demonstrate that neutralizing TGF‐β with 1D11 increases osteoblast numbers while simultaneously decreasing active osteoclasts in the marrow, resulting in a profound increase in bone volume and quality, similar to that seen in parathyroid hormone (PTH)–treated rodent studies. © 2010 American Society for Bone and Mineral Research.
doi_str_mv 10.1002/jbmr.139
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source Wiley-Blackwell Journals
subjects Animals
Antibodies - pharmacology
Biomechanical Phenomena - drug effects
biomechanics
Bone and Bones - drug effects
Bone and Bones - pathology
bone histomorphometry
Male
Mice
Mice, Inbred C57BL
Organ Size - drug effects
raman microspectroscopy
Signal Transduction - drug effects
TGF‐β
Transforming Growth Factor beta - immunology
Transforming Growth Factor beta - metabolism
treatments: novel entities
title Inhibition of TGF‐β signaling by 1D11 antibody treatment increases bone mass and quality in vivo
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