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Vol. 9, Issue 7, 1903-1918, July 1998
during Bone Remodeling
§
and
*Departments of Growth and Development,
Bone remodeling depends on the spatial and temporal coupling of
bone formation by osteoblasts and bone resorption by osteoclasts; however, the molecular basis of these inductive interactions is unknown. We have previously shown that osteoblastic overexpression of
TGF-Biochemistry
and Biophysics,
¶Anatomy, and
Pediatrics,
§Programs in Cell Biology and Developmental Biology,
University of California at San Francisco, San Francisco,
California 94143
2 in transgenic mice deregulates bone remodeling and leads to an
age-dependent loss of bone mass that resembles high-turnover osteoporosis in humans. This phenotype implicates TGF-2 as a physiological regulator of bone remodeling and raises the question of
how this single secreted factor regulates the functions of osteoblasts
and osteoclasts and coordinates their opposing activities in vivo. To
gain insight into the physiological role of TGF- in bone remodeling,
we have now characterized the responses of osteoblasts to TGF- in
these transgenic mice. We took advantage of the ability of alendronate
to specifically inhibit bone resorption, the lack of osteoclast
activity in c-fos
/ mice, and a new
transgenic mouse line that expresses a dominant-negative form of the
type II TGF- receptor in osteoblasts. Our results show that TGF-
directly increases the steady-state rate of osteoblastic differentiation from osteoprogenitor cell to terminally differentiated osteocyte and thereby increases the final density of osteocytes embedded within bone matrix. Mice overexpressing TGF-2 also have increased rates of bone matrix formation; however, this activity does
not result from a direct effect of TGF- on osteoblasts, but is more
likely a homeostatic response to the increase in bone resorption caused
by TGF-. Lastly, we find that osteoclastic activity contributes to
the TGF--induced increase in osteoblast differentiation at sites of
bone resorption. These results suggest that TGF- is a
physiological regulator of osteoblast differentiation and acts as a
central component of the coupling of bone formation to resorption
during bone remodeling.
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