van der Pluijm G, Most W, van der Wee-Pals L, de Groot H, Papapoulos S, Löwik C
Department of Endocrinology and Metabolic Diseases, University Hospital, Leiden, The Netherlands.
Endocrinology. 1991 Sep;129(3):1596-604. doi: 10.1210/endo-129-3-1596.
The multifunctional cytokine tumor necrosis factor-alpha (TNF alpha) stimulates osteoclastic resorption. It is not known which steps in osteoclast formation are affected by TNF alpha. We have investigated the effects of recombinant human TNF alpha (rhTNF alpha) 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 alpha at concentrations between 0.01-50 ng/ml (3 x 10(-13) to 1.5 x 10(-9) M) 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) rhTNF alpha 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 rhTNF alpha, resorption was inhibited. In experiments in which irradiation was used to block replication, it was found that TNF alpha 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 relatively 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-(1-84) stimulated resorption independent of proliferation by enhancing the differentiation of postmitotic osteoclast precursors and activating mature osteoclasts. In conclusion, the effects of TNF alpha on osteoclastic resorption are dependent on the stage of osteoclast development and the concentrations applied.
多功能细胞因子肿瘤坏死因子-α（TNFα）可刺激破骨细胞的吸收作用。目前尚不清楚破骨细胞形成过程中的哪些步骤会受到TNFα的影响。我们在两种不同的体外吸收系统中研究了重组人TNFα（rhTNFα）对破骨细胞发育和破骨细胞吸收的影响，这两种系统分别以破骨细胞发育的不同阶段为特征。此外，还将这些影响与牛甲状旁腺激素（1-84）[bovine PTH-(1-84)]的影响进行了比较。浓度在0.01 - 50 ng/ml（3×10⁻¹³至1.5×10⁻⁹ M）之间的rhTNFα，并未改变成熟破骨细胞的活性，这一活性是以胎鼠桡骨中⁴⁵Ca的释放量来衡量的。在依赖破骨细胞前体的系统（胎鼠掌骨）中，rhTNFα具有双相效应。从0.01 ng/ml起，它能剂量依赖性地刺激吸收作用，在0.5 ng/ml时达到最大反应。在浓度高于10 ng/ml的rhTNFα作用下，吸收作用受到抑制。在使用辐射来阻断复制的实验中发现，TNFα在低浓度和高浓度时均能刺激破骨细胞前体的增殖。因此，在相对较低的浓度下，钙化基质中会形成更多的破骨细胞，同时⁴⁵Ca的释放量也会增加。然而，在相对较高的浓度下，破骨细胞前体的增加并未导致吸收作用增强，因为假定的破骨细胞前体停滞在了骨膜中。相比之下，牛甲状旁腺激素（1-84）通过增强有丝分裂后破骨细胞前体的分化并激活成熟破骨细胞，从而刺激吸收作用，且与增殖无关。总之，TNFα对破骨细胞吸收的影响取决于破骨细胞的发育阶段和所应用的浓度。
