title: Inhibition of TGF-β signaling by 1D11 antibody treatment increases bone mass and quality in vivo.
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.
authors.affiliation: Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. James.Edwards@Vanderbilt.edu
authors.forename: James R
authors.initials: JR
authors.lastname: Edwards
authors.forename: Jeffry S
authors.initials: JS
authors.lastname: Nyman
authors.forename: Seint T
authors.initials: ST
authors.lastname: Lwin
authors.forename: Megan M
authors.initials: MM
authors.lastname: Moore
authors.forename: Javier
authors.initials: J
authors.lastname: Esparza
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: O'Quinn
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Hart
authors.forename: Swati
authors.initials: S
authors.lastname: Biswas
authors.forename: Chetan A
authors.initials: CA
authors.lastname: Patil
authors.forename: Scott
authors.initials: S
authors.lastname: Lonning
authors.forename: Anita
authors.initials: A
authors.lastname: Mahadevan-Jansen
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Mundy
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D001696:Biomechanical Phenomena / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000906:Antibodies; D016212:Transforming Growth Factor beta