de la Mata J, Uy H L, Guise T A, Story B, Boyce B F, Mundy G R, Roodman G D
Department of Medicine, University of Texas Health Science Center, San Antonio 78284, USA.
J Clin Invest. 1995 Jun;95(6):2846-52. doi: 10.1172/JCI117990.
Tumors frequently induce the multifunctional cytokine IL-6, which has been linked to several paraneoplastic syndromes, most notably cachexia. IL-6 stimulates osteoclast formation, causes mild hypercalcemia, and is produced by bone cells in vitro upon exposure to systemic hormones. Since IL-6 is produced together with parathyroid hormone-related protein (PTH-rP) in some patients with cancer, we tested the hypothesis that production of IL-6 potentiates the effects of PTH-rP on Ca2+ homeostasis and osteoclastic bone resorption and examined potential mechanisms for these interactions in vivo. Chinese hamster ovarian (CHO) cells stably transfected with cDNAs for IL-6 (CHO/IL-6) and PTH-rP sense (CHO/PTH-rP) or antisense (CHO/PTH-rP AS) were inoculated intramuscularly into nude mice. Experimental groups included CHO/IL-6 plus CHO/PTH-rP; CHO/IL-6 plus CHO/PTH-rP AS; CHO/IL-6 alone; and CHO/PTH-rP alone. Blood ionized Ca2+ was measured on days 0, 7, 10, 12, and 13. Three different developmental stages in the osteoclast lineage were examined at day 13: the early multipotential precursor, granulocyte macrophage colony-forming units (CFU-GM); more mature mononuclear osteoclast precursors, assessed by their capacity to form tartrate-resistant acid phosphatase-positive multinucleated cells in marrow cultures; and mature osteoclasts, assessed by histomorphometry. IL-6 increased CFU-GM but not bone resorption or Ca2+. In contrast, PTH-rP induced hypercalcemia and bone resorption and increased multinucleated osteoclasts and more mature precursors cells, but not CFU-GM. However, mice treated with both IL-6 and PTH-rP had very marked hypercalcemia and osteoclastosis as well as an increase in the number of both CFU-GM and mature osteoclast precursors. These data demonstrate that IL-6 enhances PTH-rP-mediated hypercalcemia and bone resorption, most likely by increasing the pool of early osteoclast precursors that in turn can differentiate to mature osteoclasts. We conclude that IL-6 stimulatory effects on osteoclast precursors may enhance the effects of other bone resorption factors that act at later stages in the osteoclast lineage.
肿瘤常常诱导多功能细胞因子白细胞介素 -6（IL -6）的产生，IL -6与多种副肿瘤综合征有关，最显著的是恶病质。IL -6刺激破骨细胞形成，导致轻度高钙血症，并且骨细胞在体外暴露于全身性激素时会产生IL -6。由于在一些癌症患者中IL -6与甲状旁腺激素相关蛋白（PTH -rP）一起产生，我们检验了这样的假设，即IL -6的产生会增强PTH -rP对钙离子稳态和破骨细胞性骨吸收的作用，并在体内研究了这些相互作用的潜在机制。将稳定转染了IL -6 cDNA（CHO/IL -6）和PTH -rP正义链（CHO/PTH -rP）或反义链（CHO/PTH -rP AS）的中国仓鼠卵巢（CHO）细胞肌肉注射到裸鼠体内。实验组包括CHO/IL -6加CHO/PTH -rP；CHO/IL -6加CHO/PTH -rP AS；单独的CHO/IL -6；以及单独的CHO/PTH -rP。在第0、7、10、12和13天测量血液中的离子钙。在第13天检查破骨细胞谱系的三个不同发育阶段：早期多能前体，粒细胞巨噬细胞集落形成单位（CFU -GM）；更成熟的单核破骨细胞前体，通过其在骨髓培养物中形成抗酒石酸酸性磷酸酶阳性多核细胞的能力进行评估；以及成熟破骨细胞，通过组织形态计量学进行评估。IL -6增加了CFU -GM，但没有增加骨吸收或钙离子水平。相反，PTH -rP诱导了高钙血症和骨吸收，并增加了多核破骨细胞和更成熟的前体细胞，但没有增加CFU -GM。然而，同时用IL -6和PTH -rP处理的小鼠出现了非常明显的高钙血症和破骨细胞增多症，以及CFU -GM和成熟破骨细胞前体数量的增加。这些数据表明，IL -6增强了PTH -rP介导的高钙血症和骨吸收，很可能是通过增加早期破骨细胞前体池，而这些前体反过来又可以分化为成熟破骨细胞。我们得出结论，IL -6对破骨细胞前体的刺激作用可能会增强其他在破骨细胞谱系后期起作用的骨吸收因子的作用。
