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, and Tumor Necrosis Factor- Increase Human Osteoclast Formation and Bone Resorption in Vitro1
Department of Histopathology, Imperial College School of Medicine at St. Mary’s, London W2 1PG, United Kingdom
Address all correspondence and requests for reprints to: Adrienne M. Flanagan, Department of Histopathology, Imperial College School of Science, Technology and Medicine at St. Mary’s, Norfolk Place, London W2 1PG, United Kingdom. E-mail: a.flanagan{at}ic.ac.uk
Prostaglandin E2 (PGE2) and the cytokines
interleukin (IL) 1
and tumor necrosis factor (TNF) increase bone
resorption in vivo, but the effect of these agents on
osteoclastic bone resorption has never been studied in an in
vitro human system. Our recently described human bone marrow
culture system, in which osteoclasts are generated (vitronectin and
calcitonin receptor-positive cells which resorb bone), was used to
study the effects of these agents. Addition of indomethacin to
macrophage colony-stimulating factor (M-CSF)-treated cultures nearly
abolished osteoclast parameters, indicating that prostaglandins are
virtually essential for human osteoclast formation. Additionally,
PGE2 dose responsively increased osteoclast numbers and
bone resorption. The effects of M-CSF and PGE2 are
independent, as demonstrated by unaltered PGE2
concentrations in culture supernatants in spite of the dose-responsive
increase in osteoclast parameters in response to M-CSF. The generation
of osteoclasts in the presence of PGE2 occurred in favor of
CD 14-positive macrophage formation.
IL 1 and TNF increased osteoclast parameters in a dose-responsive
manner. Maximum stimulation yielded culture supernatant levels of
PGE2 approximately the same as those concentrations of
exogenous PGE2 that dramatically induced osteoclast
formation. This osteoclast-inducing effect was inhibited both by
indomethacin and by the specific inhibitor of inducible prostaglandin
G/H synthase, NS-398, and this was reversed by addition of exogenous
PGE2. These results demonstrate unequivocally that IL 1
and TNF enhance human osteoclast formation and suggest that they
mediate their effects through PGE2.
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