E. Filvaroff et al., Inhibition of TGF-beta receptor signaling in osteoblasts leads to decreased bone remodeling and increased trabecular bone mass, DEVELOPMENT, 126(19), 1999, pp. 4267-4279
Transforming growth factor-beta (TGF-beta) is abundant in bone matrix and h
as been shown to regulate the activity of osteoblasts and osteoclasts in vi
tro. To explore the role of endogenous TGF-beta in osteoblast function in v
ivo, we have inhibited osteoblastic responsiveness to TGF-beta in transgeni
c mice by expressing a cytoplasmically truncated type II TGF-beta receptor
from the osteocalcin promoter, These transgenic mice develop an age-depende
nt increase in trabecular bone mass, which progresses up to the age of 6 mo
nths, due to an imbalance between bone formation and resorption during bone
remodeling. Since the rate of osteoblastic bone formation was not altered,
their increased trabecular bone mass is likely due to decreased bone resor
ption by osteoclasts, Accordingly, direct evidence of reduced osteoclast ac
tivity was found in transgenic mouse skulls, which had less cavitation and
fewer mature osteoclasts relative to skulls of wild-type mice. These bone r
emodeling defects resulted in altered biomechanical properties, The femurs
of transgenic mice were tougher, and their vertebral bodies were stiffer an
d stronger than those of wild-type mice. Lastly, osteocyte density was decr
eased in transgenic mice, suggesting that TGF-beta signaling in osteoblasts
is required for normal osteoblast differentiation in vivo, Our results dem
onstrate that endogenous TGF-beta acts directly on osteoblasts to regulate
bone remodeling, structure and biomechanical properties.