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

J Bone Miner Res. 2010 Nov;25(11):2419-26. doi: 10.1002/jbmr.139.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / pharmacology*
  • Biomechanical Phenomena / drug effects
  • Bone and Bones / drug effects*
  • Bone and Bones / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Organ Size / drug effects
  • Signal Transduction / drug effects*
  • Transforming Growth Factor beta / immunology*
  • Transforming Growth Factor beta / metabolism*

Substances

  • Antibodies
  • Transforming Growth Factor beta