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 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.
Edwards
James R
JR
Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. James.Edwards@Vanderbilt.edu
Nyman
Jeffry S
JS
Lwin
Seint T
ST
Moore
Megan M
MM
Esparza
Javier
J
O'Quinn
Elizabeth C
EC
Hart
Andrew J
AJ
Biswas
Swati
S
Patil
Chetan A
CA
Lonning
Scott
S
Mahadevan-Jansen
Anita
A
Mundy
Gregory R
GR
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*
D000906:Antibodies; D016212:Transforming Growth Factor beta