Oncostatin M enhances osteoprotegerin synthesis but reduces macrophage colony‑stimulating factor synthesis in bFGF‑stimulated osteoblast‑like cells.

IF 2.4 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Experimental and therapeutic medicine Pub Date : 2023-11-24 DOI:10.3892/etm.2023.12322
Tomoyuki Hioki, Junko Tachi, Kyohei Ueda, Rie Matsushima-Nishiwaki, Hiroki Iida, Osamu Kozawa, Haruhiko Tokuda
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Abstract

Bone remodeling is tightly controlled by various factors, including hormones, autacoids and cytokines. Among them, oncostatin M (OSM) is a multifunctional cytokine produced by osteal macrophages, which serves as an essential modulator of bone remodeling. Macrophage colony-stimulating factor (M-CSF) and osteoprotegerin are secreted by osteoblasts, and also have pivotal roles in the regulation of the bone remodeling process. The binding of basic fibroblast growth factor (bFGF), a key regulator of bone remodeling, to the corresponding receptor [fibroblast growth factor receptor (FGFR)] triggers the dimerization and activation of FGFRs, which causes the phosphorylation of FGFR substrates and subsequent activation of downstream effectors, including mitogen-activated protein kinases (MAPKs), via Grb2. bFGF can activate MAPKs, resulting in the synthesis of osteoprotegerin and vascular endothelial growth factor in osteoblast-like MC3T3-E1 cells. In the present study, the effects of OSM on bFGF-induced osteoblast activation were investigated in the synthesis of osteoprotegerin and M-CSF in osteoblasts. The release of osteoprotegerin and M-CSF were analyzed using ELISA. The mRNA expression levels of osteoprotegerin and M-CSF were analyzed using reverse transcription-quantitative PCR. Phosphorylation of p38 MAPK, stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p44/p42 MAPK was assessed using western blotting. OSM enhanced bFGF-induced osteoprotegerin release and bFGF-stimulated mRNA expression of osteoprotegerin. By contrast, OSM suppressed the bFGF-induced release of M-CSF and bFGF-stimulated mRNA expression of M-CSF. SB203580, a p38 MAPK inhibitor, and SP600125, a SAPK/JNK inhibitor, suppressed the bFGF-stimulated M-CSF release, whereas PD98059, an upstream kinase inhibitor of p44/p42 MAPK, failed to suppress the M-CSF release stimulated by bFGF. Furthermore, OSM enhanced the bFGF-induced phosphorylation of p38 MAPK, but attenuated the bFGF-stimulated phosphorylation of SAPK/JNK. By contrast, OSM had little effect on the bFGF-induced phosphorylation of p44/p42 MAPK. SB203580 markedly reduced the amplification of bFGF-stimulated osteoprotegerin release enhanced by OSM. These results strongly suggested that OSM may possess divergent effects on bFGF-induced osteoblast activation, upregulation of p38 MAPK and downregulation of SAPK/JNK, leading to the amplification of osteoprotegerin synthesis and the attenuation of M-CSF synthesis.
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Oncostatin M 可增强 bFGF 刺激的成骨细胞样细胞中的骨保护素合成,但会减少巨噬细胞集落刺激因子的合成。
骨重塑受到各种因素的严格控制,包括激素、自体类固醇和细胞因子。其中,OSM(oncostatin M)是一种由骨膜巨噬细胞产生的多功能细胞因子,是骨重塑的重要调节因子。巨噬细胞集落刺激因子(M-CSF)和骨蛋白激酶(osteoprotegerin)由成骨细胞分泌,在调节骨重塑过程中也起着举足轻重的作用。碱性成纤维细胞生长因子(bFGF)是骨重塑的一个关键调节因子,它与相应的受体[成纤维细胞生长因子受体(FGFR)]结合会引发 FGFR 的二聚化和活化,从而导致 FGFR 底物磷酸化,随后通过 Grb2 激活下游效应因子,包括丝裂原活化蛋白激酶(MAPK)。bFGF 可激活 MAPKs,导致成骨细胞样 MC3T3-E1 细胞合成骨保护素和血管内皮生长因子。在本研究中,OSM 对 bFGF 诱导的成骨细胞活化的影响主要体现在成骨细胞中骨蛋白gerin 和 M-CSF 的合成上。使用 ELISA 分析了骨保护gerin 和 M-CSF 的释放。使用逆转录定量 PCR 分析了骨保护gerin 和 M-CSF 的 mRNA 表达水平。p38 MAPK、应激活化蛋白激酶/c-Jun N-末端激酶(SAPK/JNK)和 p44/p42 MAPK 的磷酸化采用 Western 印迹法进行评估。OSM增强了bFGF诱导的骨保护gerin释放和bFGF刺激的骨保护gerin mRNA表达。相比之下,OSM 抑制了 bFGF 诱导的 M-CSF 释放和 bFGF 刺激的 M-CSF mRNA 表达。p38 MAPK抑制剂SB203580和SAPK/JNK抑制剂SP600125抑制了bFGF刺激的M-CSF释放,而p44/p42 MAPK上游激酶抑制剂PD98059未能抑制bFGF刺激的M-CSF释放。此外,OSM 还增强了 bFGF 诱导的 p38 MAPK 磷酸化,但减弱了 bFGF 刺激的 SAPK/JNK 磷酸化。相比之下,OSM 对 bFGF 诱导的 p44/p42 MAPK 磷酸化几乎没有影响。SB203580 显著降低了 OSM 对 bFGF 刺激的骨保护素释放的放大作用。这些结果有力地表明,OSM 可能对 bFGF 诱导的成骨细胞活化、p38 MAPK 上调和 SAPK/JNK 下调具有不同的作用,从而导致骨保护gerin 合成的增加和 M-CSF 合成的减少。
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来源期刊
Experimental and therapeutic medicine
Experimental and therapeutic medicine MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
1.50
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0.00%
发文量
570
审稿时长
1 months
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