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Inhibition of osteoblastic metalloproteinases in mice prevents bone loss induced by oestrogen deficiency
Author(s) -
Schiltz Corinne,
Marty Caroline,
de Vernejoul MarieChristine,
Geoffroy Valerie
Publication year - 2008
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.21747
Subject(s) - bone resorption , endocrinology , medicine , osteoclast , matrix metalloproteinase , bone remodeling , chemistry , in vivo , resorption , genetically modified mouse , osteoblast , transgene , biology , in vitro , receptor , biochemistry , microbiology and biotechnology , gene
Abstract Matrix metalloproteinases (MMPs) are key mediators in extra‐cellular matrix remodelling and implicated primarily in bone growth, and particularly in osteoclastic bone resorption. We hypothesise that MMPs have a role in the increased bone remodelling resulting from oestrogen deficiency. Transgenic (TG) mice overexpressing TIMP‐1 in their osteoblastic cells and their wild‐type (WT) littermates were ovariectomised. One month after surgery, bone mineral density (BMD) and bone microarchitecture were assessed. Primary cells from WT and TG mice were used to determine how TIMP‐1 affects osteoclast and osteoblastic cells. The reduction of BMD induced by ovariectomy in WT mice was not observed in the transgenic mice. The transgene overexpression also dampened the post‐ovariectomy increase in bone resorption in contrast to the WT mice. In vivo, osteoclastic surfaces and D ‐pyridinoline were not increased in TG mice, and ex vivo, the differentiation of osteoclasts from TG bone marrow precursor cells were unaffected by in vivo oestrogen deficiency or treatment. We showed also that TIMP‐1 overexpression reduces and delays the osteoblastic proliferation and differentiation respectively, and reduced the generation of the active form of TGFβ1 in the supernatant of TG osteoblasts. Our findings support the hypothesis that in vivo inhibition of osteoblastic MMPs prevented the bone loss induced by oestrogen deficiency, with a significant decrease in bone resorption. This effect was presumably resulting from (1) a direct inhibition of osteoclastic resorption activity by the TIMP‐1 and (2) the modification in the local activation of extra‐cellular signalling factors such as TGFβ1 and the OPG/RANKL ratio. J. Cell. Biochem. 104: 1803–1817, 2008. © 2008 Wiley‐Liss, Inc.