Osteal Tissue Macrophages Are Involved in Endplate Osteosclerosis through the OSM-STAT3/YAP1 Signaling Axis in Modic Changes
Osteal Tissue Macrophages Are Involved in Endplate Osteosclerosis through the OSM-STAT3/YAP1 Signaling Axis in Modic Changes
复制标题
骨组织巨噬细胞通过 Modic 变化中的 OSM-STAT3/YAP1 信号轴参与终板骨质硬化
DOI：
10.4049/jimmunol.1901001
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发表时间：
2020-08-15
影响因子：
4.4
通讯作者：
Zhao, Fengdong
中科院分区：
文献类型：
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作者：
Wang, Jiasheng;Zheng, Zeyu;Zhao, Fengdong
关键点Osteomacs与MC终板骨质增生相关。Osteomacs可通过OSM-STAT 3/YAP 1信号转导轴调控成骨。OSM阻断可防止MCs终板骨质疏松。Modic改变（MC）是腰椎退行性疾病的放射学表现。各种类型的MCs常与终板骨质疏松有关。据报道，骨组织巨噬细胞（Osteomacs）对于骨稳态和骨修复至关重要，但Osteomacs是否参与MC终板骨硬化仍不清楚。在本研究中，我们试图探讨成骨细胞在调节MC成骨中的关键作用。我们从患者标本中收集MCs，建立痤疮丙酸杆菌诱导的大鼠MCs模型，采用显微CT和免疫组化检测终板骨量和骨瘤的分布。在患者的MCs中，终板软骨下骨中的骨瘤增加，尤其是Modic II型。Modic III型终板表现为稳定的骨质疏松。在大鼠MCs模型中，骨瘤样细胞在终板区的增生区增加，而在炎症区不增加，但骨瘤样细胞的分布与骨质疏松区一致。为了进一步探讨体外培养的成骨细胞的功能，我们利用MACS技术分离了成骨细胞，发现成骨细胞分泌抑瘤素M（OSM），并通过OSM介导的酪氨酸磷酸化和STAT 3与Yes‐associated protein 1（YAP 1）的相互作用机制强烈促进成骨细胞的分化，而不是破骨细胞。STAT 3磷酸化抑制或YAP 1敲低减弱了OSM介导的成骨细胞分化。最后，我们证实了使用抗OSM中和抗体在体内阻断OSM可预防大鼠MC模型中的终板骨质疏松。总之，这些发现证实了MC中终板成骨伴随着骨瘤数量的增加，骨瘤通过OSM-STAT 3/YAP 1信号轴调节骨生成。
Key Points Osteomacs are associated with endplate osteosclerosis in MCs. Osteomacs can regulate osteogenesis through the OSM-STAT3/YAP1 signaling axis. OSM blockade prevents endplate osteosclerosis in MCs. Modic changes (MCs) are radiographic manifestations of lumbar degenerative diseases. Various types of MCs are often associated with endplate osteosclerosis. Osteal tissue macrophages (Osteomacs) were reported to be crucial for bone homeostasis and bone repair, but whether osteomacs participate in the endplate osteosclerosis in MCs remained unclear. In this study, we tried to explore the critical role of osteomacs in regulating osteogenesis in MCs. We collected MCs from patient samples and developed a Propionibacterium acnes–induced rat MCs model, using microcomputed tomography and immunohistochemistry to detect the endplate bone mass and distribution of osteomacs. In patients' MCs, osteomacs increased in endplate subchondral bone, especially in Modic type II. Endplate in Modic type III presented a stable osteosclerosis. In rat MCs model, osteomacs increased in the bone hyperplasia area but not in the inflammation area of the endplate region, whereas the distribution of osteomacs was consistent with the area of osteosclerosis. To further explore the functions of osteomacs in vitro, we isolated osteomacs using MACS technology and found osteomacs secreted oncostatin M (OSM) and strongly promoted osteoblast differentiation rather than osteoclast through the mechanism of OSM-mediated tyrosine phosphorylation and interaction of STAT3 and Yes‐associated protein 1 (YAP1). STAT3 phosphorylation inhibition or YAP1 knockdown attenuated OSM-mediated osteoblast differentiation. Finally, we confirmed that blockade of OSM in vivo using anti-OSM–neutralizing Ab prevented endplate osteosclerosis in rat MCs model. Taken together, these findings confirmed that endplate osteosclerosis in MCs was accompanied by an increased number of osteomacs, which regulated osteogenesis via the OSM-STAT3/YAP1 signaling axis.