Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China; and Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou 310016, China.
Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China; and Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou 310016, China
J Immunol. 2020 Aug 15;205(4):968-980. doi: 10.4049/jimmunol.1901001. Epub 2020 Jul 20.
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 -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.
Modic 改变（MCs）是腰椎退行性疾病的影像学表现。各种类型的 MCs 常与终板骨硬化有关。骨组织巨噬细胞（Osteomacs）被报道对骨稳态和骨修复至关重要，但 Osteomacs 是否参与 MCs 中的终板骨硬化仍不清楚。在这项研究中，我们试图探讨 Osteomacs 在调节 MCs 中的成骨作用中的关键作用。我们从患者样本中收集 MCs，并通过微计算机断层扫描和免疫组织化学检测终板骨量和 Osteomacs 的分布，建立了 - 诱导的大鼠 MCs 模型。在患者的 MCs 中，Osteomacs 在终板软骨下骨中增加，特别是在 Modic 型 II 中。Modic 型 III 的终板呈现稳定的骨硬化。在大鼠 MCs 模型中，Osteomacs 在骨增生区域增加，但不在终板区域的炎症区域增加，而 Osteomacs 的分布与骨硬化区域一致。为了进一步在体外探索 Osteomacs 的功能，我们使用 MACS 技术分离 Osteomacs，发现 Osteomacs 分泌肿瘤坏死因子（OSM），并通过 OSM 介导的酪氨酸磷酸化和 STAT3 与 Yes 相关蛋白 1（YAP1）的相互作用机制强烈促进成骨细胞分化，而不是破骨细胞。STAT3 磷酸化抑制或 YAP1 敲低减弱了 OSM 介导的成骨细胞分化。最后，我们在体内使用抗 OSM 中和 Ab 阻断 OSM，证实其阻止了大鼠 MCs 模型中的终板骨硬化。总之，这些发现证实了 MCs 中的终板骨硬化伴随着 Osteomacs 数量的增加，它们通过 OSM-STAT3/YAP1 信号轴调节成骨作用。
