INTERLEUKIN-6 ENHANCES HYPERCALCEMIA AND BONE-RESORPTION MEDIATED BY PARATHYROID HORMONE-RELATED PROTEIN IN-VIVO
INTERLEUKIN-6 ENHANCES HYPERCALCEMIA AND BONE-RESORPTION MEDIATED BY PARATHYROID HORMONE-RELATED PROTEIN IN-VIVO
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DOI：
10.1172/jci117990
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发表时间：
1995-06-01
影响因子：
15.9
通讯作者：
ROODMAN, GD
中科院分区：
文献类型：
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作者：
DELAMATA, J;UY, HL;ROODMAN, GD
肿瘤经常诱导多功能细胞因子IL-6，这与几种副肿瘤综合征有关，最明显的是恶病质。IL-6刺激破骨细胞形成，引起轻度高钙血症，并且在体外暴露于全身激素时由骨细胞产生。由于IL-6与甲状旁腺激素相关蛋白（PTH-rP）一起在一些癌症患者中产生，我们测试了IL-6的产生增强PTH-rP对Ca 2+稳态和骨细胞骨吸收的影响的假设，并检查了这些相互作用的潜在机制。将IL-6（CHO/IL-6）和PTH-rP正义（CI 10/PTH-rP）或反义（CHO/PTH-rP AS）cDNA稳定转染的中国仓鼠卵巢（CHO）细胞肌内接种到裸鼠中。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;和单独的CHO/PTH-rP。在第0、7、10、12和13天测量血液离子化Ca 2+。在第13天检测了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，通过它们在骨髓培养物中形成抗酒石酸盐酸性磷酸酶阳性多核细胞的能力来评估;和成熟破骨细胞，通过组织形态计量学评估，IL-6增加CFU-GM，但不增加骨吸收或Ca 2+。与此相反，PTH-rP诱导高钙血症和骨吸收，增加多核破骨细胞和更成熟的前体细胞，但不是CFU-GM。然而，用IL-6和PTH-rP治疗的小鼠具有非常显著的高钙血症和破骨细胞增生，以及CFU-GM和成熟破骨细胞前体的数量增加。这些数据表明，IL-6增强PTH-rP介导的高钙血症和骨吸收，最有可能是通过增加早期破骨细胞前体的池，其反过来可以分化为成熟的破骨细胞。我们的结论是，IL-6对破骨细胞前体的刺激作用可能会增强其他骨吸收因子在破骨细胞谱系后期发挥作用的作用。
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 (CIIO/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.