Two distinct effects of recombinant human tumor necrosis factor-a on osteoclast development and subsequent resorption of mineralized matrix

GVANDER PLUIJM, W MOST… - …, 1991 - academic.oup.com
GVANDER PLUIJM, W MOST, LVANDER WEE-PALS, HDE GROOT, S PAPAPOULOS…
Endocrinology, 1991academic.oup.com
The multifunctional cytokine tumor necrosis factor-α (TNF α) stimulates osteoclastic
resorption. It is not known which steps in osteoclast formation are affected by TNF α. We
have investigated the effects of recombinant human TNF α (rhTNF α) on osteoclast
development and osteoclastic resorption in two different in vitro resorption systems which
are each characterized by a different stage of development of the osteoclast. The effects
were further compared to those of bovine PTH-1–84). rhTNF α at concentrations between …
The multifunctional cytokine tumor necrosis factor-α (TNFα) stimulates osteoclastic resorption. It is not known which steps in osteoclast formation are affected by TNFα. We have investigated the effects of recombinant human TNFα (rhTNFα) on osteoclast development and osteoclastic resorption in two different in vitro resorption systems which are each characterized by a different stage of development of the osteoclast. The effects were further compared to those of bovine PTH-1–84).
rhTNFα at concentrations between 0.01-50 ng/ml (3 × 10−13 to 1.5 × 10−9m) did not alter the activity of mature osteoclasts, measured as 45Ca release in fetal mouse radii.
In the osteoclast precursor-dependent system (fetal mouse metacarpals) rhTNFα had a biphasic effect. It stimulated resorption dose-dependently from 0.01 ng/ml onward, with a maximal response at 0.5 ng/ml. At concentrations above 10 ng/ml rhTNFα, resorption was inhibited. In experiments in which irradiation was used to block replication, it was found that TNFα stimulates the proliferation of osteoclast progenitors at both low and high concentrations. As a result, at relatively low concentrations, more osteoclasts were formed in the calcified matrix, coinciding with an increased release of 45Ca. However, at relativly high concentrations, the increase in osteoclast progenitors did not lead to increased resorption, since the putative osteoclast progenitors were arrested in the periosteum. In comparison, bovine PTH-(l–84) stimulated resorption independent of proliferation by enhancing the differentiation of postmitotic osteoclast precursors and activating mature osteoclasts.
In conclusion, the effects of TNFα on osteoclastic resorption are dependent on the stage of osteoclast development and the concentrations applied. (Endocrinology 129: 1596–1604, 1991)
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