Soluble Sema4D cleaved from osteoclast precursors by TACE suppresses osteoblastogenesis.
Soluble Sema4D cleaved from osteoclast precursors by TACE suppresses osteoblastogenesis.
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DOI：
10.1111/jcmm.17416
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发表时间：
2023-06
影响因子：
5.3
通讯作者：
中科院分区：
文献类型：
--
作者：
骨重建由破骨细胞和成骨细胞之间的协调通信介导，其部分由偶联和反偶联因子调节。在正式已知的抗偶联因子中，由破骨细胞产生的脑信号蛋白4D（Sema 4D）在下调成骨细胞生成中起关键作用。Sema 4D以膜结合和可溶形式产生;然而，负责从破骨细胞产生sSema 4D的机制尚不清楚。Sema 4D、TACE和MT 1 ‐MMP均在RANKL引发的破骨细胞前体表面表达。然而，仅Sema 4D和TACE共定位，而非Sema 4D和MT 1 ‐MMP。当TACE和MT 1-MMP被siRNA化学抑制或抑制时，发现TACE更参与脱落Sema 4D。抗TACE mAb抑制破骨细胞前体释放sSema 4D约90%。通过碱性磷酸酶活性测定，从破骨细胞前体中收集的上清液（OC-sup）抑制了MC 3 T3-E1细胞的成骨细胞生成，但从抗TACE-mAb处理的破骨细胞前体中收集的OC-sup以补偿sSema 4D减少的方式恢复了成骨细胞生成活性。最后，全身给予抗TACE mAb下调了临界大小骨缺损小鼠模型中sSema 4D的生成，而局部注射重组sSema 4D至抗TACE mAb治疗的缺损处上调了局部成骨细胞生成。因此，提出了一种新的途径，即TACE介导的破骨细胞前体上表达的Sema 4D脱落产生功能活性sSema 4D以抑制成骨细胞生成。
Bone remodelling is mediated by orchestrated communication between osteoclasts and osteoblasts which, in part, is regulated by coupling and anti‐coupling factors. Amongst formally known anti‐coupling factors, Semaphorin 4D (Sema4D), produced by osteoclasts, plays a key role in downmodulating osteoblastogenesis. Sema4D is produced in both membrane‐bound and soluble forms; however, the mechanism responsible for producing sSema4D from osteoclasts is unknown. Sema4D, TACE and MT1‐MMP are all expressed on the surface of RANKL‐primed osteoclast precursors. However, only Sema4D and TACE were colocalized, not Sema4D and MT1‐MMP. When TACE and MT1‐MMP were either chemically inhibited or suppressed by siRNA, TACE was found to be more engaged in shedding Sema4D. Anti‐TACE‐mAb inhibited sSema4D release from osteoclast precursors by ~90%. Supernatant collected from osteoclast precursors (OC‐sup) suppressed osteoblastogenesis from MC3T3‐E1 cells, as measured by alkaline phosphatase activity, but OC‐sup harvested from the osteoclast precursors treated with anti‐TACE‐mAb restored osteoblastogenesis activity in a manner that compensates for diminished sSema4D. Finally, systemic administration of anti‐TACE‐mAb downregulated the generation of sSema4D in the mouse model of critical‐sized bone defect, whereas local injection of recombinant sSema4D to anti‐TACE‐mAb‐treated defect upregulated local osteoblastogenesis. Therefore, a novel pathway is proposed whereby TACE‐mediated shedding of Sema4D expressed on the osteoclast precursors generates functionally active sSema4D to suppress osteoblastogenesis.
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