Inhibition of TGF-β Signaling by 1D11 Antibody Treatment Increases Bone Mass and Quality In Vivo

Transforming growth factor beta (TGF-beta) is an abundant bone matrix protein that influences osteoblast and osteoclast interactions to control bone remodeling As such TGF beta 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 beta inhibition in vivo we used an antibody (1D11) specifically directed at all three isoforms of TGF beta Normal mice were treated with 1D11 or control antibody (4 weeks) and cortical and trabecular bone was assessed by micro computed tomographic (mu CT) 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-beta 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 beta 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-beta 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 (C) 2010 American Society for Bone and Mineral Research