Oncostatin M stimulates prostaglandin D2-induced osteoprotegerin and interleukin-6 synthesis in osteoblasts

Gen Kuroyanagi , Tomoyuki Hioki , Junko Tachi , Rie Matsushima-Nishiwaki , Hiroki Iida , Osamu Kozawa , Haruhiko Tokuda
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Abstract

Oncostatin M produced by osteal macrophages plays a significant role in fracture healing. Osteoprotegerin (OPG) secreted by osteoblasts, binds to the receptor activator of nuclear factor-κB (RANK) ligand (RANKL) as a decoy receptor and prevents RANKL from binding to RANK, resulting in bone resorption suppression. Interleukin-6 (IL-6) is a pro-inflammatory cytokine and generally regulates bone resorption. However, accumulating evidence suggests that IL-6 plays pivotal roles in bone formation. We previously showed that prostaglandin D2 (PGD2) induces OPG synthesis by activating p38 mitogen-activated protein (MAP) kinase, stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and p44/p42 MAP kinase in osteoblast-like MC3T3-E1 cells. Furthermore, we demonstrated that PGD2 stimulates IL-6 synthesis by activating p38 MAP kinase and p44/p42 MAP kinase in MC3T3-E1 cells. In the present study, we investigated whether oncostatin M affects PGD2-stimulated OPG and IL-6 synthesis in MC3T3-E1 cells through MAP kinase activation. The osteoblast-like MC3T3-E1 cells and normal human osteoblasts were treated with oncostatin M and subsequently stimulated with PGD2. Consequently, oncostatin M significantly increased the PGD2-stimulated OPG and IL-6 release in both cells. Oncostatin M significantly enhanced mRNA expression levels of OPG and IL-6 induced by PGD2 similarly in both cells. Regarding the signaling mechanism, oncostatin M did not affect the phosphorylation of p38 MAP kinase, SAPK/JNK, and p44/p42 MAP kinase. Our results suggest that oncostatin M upregulates the PGD2-stimulated OPG and IL-6 synthesis in osteoblasts and therefore affects bone remodeling. However, OPG and IL-6 synthesis are not mediated through p38 MAP kinase, p44/p42 MAP kinase, or SAPK/JNK pathways.

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抑瘤素M刺激前列腺素D2诱导的成骨细胞骨保护素和白细胞介素-6的合成
骨巨噬细胞产生的肿瘤抑制素M在骨折愈合中起着重要作用。成骨细胞分泌的骨保护蛋白(OPG)作为诱饵受体与核因子κB受体激活剂配体(RANKL)结合,阻止RANKL与RANK结合,从而抑制骨吸收。白细胞介素-6(IL-6)是一种促炎细胞因子,通常调节骨吸收。然而,越来越多的证据表明,IL-6在骨形成中起着关键作用。我们先前发现前列腺素D2(PGD2)通过激活成骨细胞样MC3T3-E1细胞中的p38丝裂原活化蛋白(MAP)激酶、应激活化蛋白激酶/c-Jun N-末端激酶(SAPK/JNK)和p44/p42 MAP激酶来诱导OPG合成。此外,我们证明PGD2通过激活MC3T3-E1细胞中的p38MAP激酶和p44/p42MAP激酶来刺激IL-6的合成。在本研究中,我们研究了抑癌素M是否通过MAP激酶激活影响MC3T3-E1细胞中PGD2刺激的OPG和IL-6的合成。成骨细胞样MC3T3-E1细胞和正常人成骨细胞用生长抑素M处理,随后用PGD2刺激。因此,肿瘤学抑制素M显著增加了PGD2刺激的两种细胞中OPG和IL-6的释放。在两种细胞中,类似地,抑瘤素M显著增强PGD2诱导的OPG和IL-6的mRNA表达水平。关于信号传导机制,肿瘤学抑制素M不影响p38MAP激酶、SAPK/JNK和p44/p42MAP激酶的磷酸化。我们的研究结果表明,肿瘤学抑制素M上调PGD2刺激的成骨细胞中OPG和IL-6的合成,从而影响骨重塑。然而,OPG和IL-6的合成不是通过p38MAP激酶、p44/p42MAP激酶或SAPK/JNK途径介导的。
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来源期刊
Prostaglandins, leukotrienes, and essential fatty acids
Prostaglandins, leukotrienes, and essential fatty acids Clinical Biochemistry, Endocrinology, Diabetes and Metabolism
CiteScore
5.30
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0.00%
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0
审稿时长
64 days
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