Characterization of the bone-resorptive effect of interleukin-11 in cultured mouse calvarial bones
Characterization of the bone-resorptive effect of interleukin-11 in cultured mouse calvarial bones
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DOI：
10.1016/s8756-3282(02)00784-6
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发表时间：
2002-07-01
期刊：
影响因子：
4.1
通讯作者：
Lerner, UH
中科院分区：
文献类型：
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作者：
Ahlen, J;Andersson, S;Lerner, UH
白细胞介素-11 (IL-11) 是一种基质细胞衍生的细胞因子，可以增强破骨细胞的形成并刺激骨吸收。在本研究中，研究了IL-11在小鼠颅骨中的再吸收作用的特征。重组小鼠 IL-11 和人 IL-11 都会对预先标记的小鼠颅盖释放 Ca-45 产生浓度和时间依赖性刺激。在 0.7 ng/mL（大约 40 pmol/L）时获得半最大响应。小鼠和人类 IL-11 也刺激 [H-3]脯氨酸标记的骨骼释放 H-3。 IL-11最大有效浓度引起的Ca-45和H-3释放量（1.4-1.6倍）小于甲状旁腺激素（PTH）最大浓度引起的刺激（2.5-4.0倍）。 IL-11 释放 Ca-45 不受有丝分裂抑制剂、羟基脲和阿非迪霉素的影响。除了骨吸收外，IL-11 还引起颅盖中前列腺素 E-2 (PGE(2)) 生物合成的小幅增强（1.5-2.0 倍），但对环氧合酶-1 和 -2 或胞质磷脂酶 A(2) 的 mRNA 表达没有影响。吲哚美辛和氟比洛芬消除了 PGE(2) 的形成并部分减少了 IL-11 刺激的 Ca-45 释放。当将小鼠白细胞介素 4 (IL-4) 或白细胞介素 13 (IL-13) 添加到用 IL-11 处理的颅盖中时，Ca-45 的释放受到抑制。 IL-11 引起的吸收也被抗小鼠糖蛋白 130 (gp130) 和中和 IL-11 的抗体抑制，但这些药物对 PTH 或 1,25(OH)(2) 维生素 D-3 (D-3) 引起的 Ca-45 释放没有影响。实时定量聚合酶链反应 (PCR) 分析 (TaqMan PCR) 和半定量逆转录聚合酶链反应 (RT-PCR) 表明，IL-11 导致核因子 kappaB 配体受体激活剂 (RANKL) 和骨保护素 (OPG) mRNA 浓度依赖性增强，而不影响 RANK 的 mRNA 表达。小鼠 RANKL 刺激颅骨中 Ca-45 的释放。 RANKL 和 IL-11 的刺激作用被小鼠 OPG 抑制。这些数据表明，IL-11 通过独立于细胞增殖的机制刺激小鼠颅骨中的破骨细胞吸收；部分依赖前列腺素生物合成；对 IL-4、IL-13 和 OPG 的抑制敏感；并与 RANKL 和 OPG 表达增强相关。此外，未发现IL-11在颅骨中其他促钙剂刺激的吸收中发挥重要作用。
Interleukin-11 (IL-11) is a stromal cell-derived cytokine that can enhance osteoclast formation and stimulate bone resorption. In the present study, the characteristics of the resorptive effect of IL-11 in mouse calvarial bones were investigated. Both recombinant mouse IL-11 and human IL-11 caused concentration- and time-dependent stimulations of Ca-45 release from prelabeled mouse calvariae. Half-maximal responses were obtained at 0.7 ng/mL (approximate to40 pmol/L). Mouse and human IL-11 also stimulated release of H-3 from [H-3]proline-labeled bones. The magnitude of the Ca-45 and H-3 release (1.4-1.6-fold) caused by a maximally effective concentration of IL-11 was less than the stimulation (2.5-4.0-fold) elicited by a maximum concentration of parathyroid hormone (PTH). Release of Ca-45 by IL-11 was unaffected by the mitotic inhibitors, hydroxyurea and aphidicolin. In addition to resorption of bone, IL-11 caused a small (1.5-2.0-fold) enhancement of prostaglandin E-2 (PGE(2)) biosynthesis in calvariae, but had no effect on the mRNA expression of cyclooxygenase-1 and -2, or cytosolic phospholipase A(2). Indomethacin and flurbiprofen abolished the formation of PGE(2) and partially reduced Ca-45 release stimulated by IL-11. When either mouse interleukin-4 (IL-4) or interleukin-13 (IL-13) was added to calvariae treated with IL-11, Ca-45 release was inhibited. Resorption caused by IL-11 was also inhibited by both anti-mouse glycoprotein 130 (gp130) and an antibody neutralizing IL-11, but these agents had no effect on Ca-45 release caused by PTH or 1,25(OH)(2)vitamin D-3 (D-3). Real-time, quantitative polymerase chain reaction (PCR) analysis (TaqMan PCR) and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) demonstrated that IL-11 caused concentration-dependent enhancements of receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) mRNA, without affecting the mRNA expression of RANK. Mouse RANKL stimulated Ca-45 release in the calvarial bones. The stimulatory effects of RANKL and IL-11 were inhibited by mouse OPG. These data demonstrate that IL-11 stimulates osteoclastic resorption in mouse calvariae by mechanisms that are independent of cell proliferation; partially dependent on prostaglandin biosynthesis; sensitive to inhibition by IL-4, IL-13, and OPG; and associated with enhanced expression of RANKL and OPG. In addition, IL-11 was not found to play an essential role in resorption stimulated by other calciotropic agents in calvariae.