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J. Biol. Chem., Vol. 277, Issue 46, 44061-44067, November 15, 2002
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From the Nordic Bioscience A/S, Center for Clinical and Basic
Research, Herlev/Ballerup, Herlev DK-2730,
Denmark
Upon termination of bone matrix synthesis,
osteoblasts either undergo apoptosis or differentiate into osteocytes
or bone lining cells. In this study, we investigated the role of matrix
metalloproteinases (MMPs) and growth factors in the differentiation of
osteoblasts into osteocytes and in osteoblast apoptosis. The mouse
osteoblast cell line MC3T3-E1 and primary mouse calvarial osteoblasts
were either grown on two-dimensional (2-D) collagen-coated surfaces, where they morphologically resemble flattened, cuboidal bone lining cells, or embedded in three-dimensional (3-D) collagen gels, where they
resemble dendritic osteocytes constituting a network of cells. When
MC3T3-E1 osteoblasts were grown in a 3-D matrix in the presence of an
MMP inhibitor (GM6001), the cell number was
dose-dependently reduced by approximately 50%, whereas no
effect was observed on a 2-D substratum. In contrast, the murine mature
osteocyte cell line, MLO-Y4, was unaffected by GM6001 under all culture
conditions. According to TUNEL assay, the osteoblast apoptosis was
increased 2.5-fold by 10 µM GM6001. To investigate
the mechanism by which MMPs mediate the survival of osteoblasts, we
examined the effect of GM6001 on MC3T3-E1 osteoblasts in the presence
of extracellular matrix components and growth factors, including
tenascin, fibronectin, laminin, collagenase-cleaved collagen, gelatin,
parathyroid hormone, basic fibroblast growth factor, vascular
epidermal growth factor, insulin-like growth factor, interleukin-1, and
latent and active transforming growth factor-
Matrix Metalloproteinase-dependent Activation of
Latent Transforming Growth Factor-
Controls the Conversion of
Osteoblasts into Osteocytes by Blocking Osteoblast
Apoptosis*
,
(TGF-). Only active
TGF-, but not latent TGF- or other agents tested, restored cell
number and apoptosis to control levels. Furthermore, we found that the
membrane type MMP, MT1-MMP, which is produced by osteoblasts, could
activate latent TGF- and that antibodies neutralizing endogenous
TGF- led to a similar decrease in cell number as GM6001. Whereas
inhibitors of other protease families did not induce osteoblast
apoptosis, an inhibitor of the p44/42 mitogen-activated protein
kinase showed the same but non-synergetic effect as GM6001. These
findings suggest that MMP-activated TGF- maintains osteoblast
survival during trans-differentiation into osteocytes by a
p44/42-dependent pathway.
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 45-44-52-52-10;
Fax: 45-44-52-52-51; E-mail: mk@nordicbioscience.com.
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