Zoledronate suppressed angiogenesis and osteogenesis by inhibiting osteoclasts formation and secretion of PDGF-BB.
Zoledronate suppressed angiogenesis and osteogenesis by inhibiting osteoclasts formation and secretion of PDGF-BB.
复制标题
唑来膦酸通过抑制破骨细胞的形成和 PDGF-BB 的分泌来抑制血管生成和骨生成
DOI：
10.1371/journal.pone.0179248
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Liao GQ
中科院分区：
文献类型：
--
作者：
Gao SY;Zheng GS;Wang L;Liang YJ;Zhang SE;Lao XM;Li K;Liao GQ
目的双磷酸盐相关性颌骨骨坏死（BRONJ）是全身应用BPs的严重并发症，其发生机制尚不清楚。近年来，破骨细胞前体分泌的血小板源性生长因子-BB（PDGF-BB）被认为具有促进血管生成和成骨的作用。本研究旨在阐明双膦酸盐是否抑制前破骨细胞释放PDGF-BB，以及这种抑制是否损害了血管生成和骨生成的耦合，这可能导致BRONJ表现。方法和结果抗酒石酸酸性磷酸酶（TRAP）染色显示唑来膦酸盐显著抑制破骨细胞形成，ELISA检测PDGF-BB分泌。与暴露于唑来膦酸盐的前破骨细胞的PDGF-BB分泌减少一致，来自细胞的条件培养基（CM）与来自未暴露的前破骨细胞的CM相比，显著诱导较少的内皮祖细胞（EPC）和间充质干细胞（MSC）迁移。与此同时，经唑来膦酸（PZ-CM）处理的破骨前体细胞的CM也抑制了EPCs的血管生成功能和MSCs向成骨细胞的分化，EPCs的小管形成实验和MSCs的碱性磷酸酶活性均证实了这一点。Western blot结果显示，与未加唑来膦酸的破骨细胞培养液相比，PZ-CM可降低EPCs中VEGF的表达，降低MSCs中OCN、RUNX 2的表达。结论唑来膦酸能抑制破骨细胞释放PDGF-BB，从而抑制血管生成和成骨。本研究结果可能部分解释了BRONJ的发病机制。
Purpose Bisphosphonates related osteonecrosis of jaw (BRONJ) is a severe complication of systemic BPs administration, the mechanism of which is still unclarified. Recently, platelet-derived growth factor-BB (PDGF-BB) secreted by preosteoclasts was reported to promote angiogenesis and osteogenesis. This study aimed to clarify whether bisphosphonates suppressed preosteoclasts releasing PDGF-BB, and whether the suppression harmed coupling of angiogenesis and osteogenesis, which could contribute to BRONJ manifestation. Methods and results Zoledronate significantly inhibited osteoclast formation by tartrate-resistant acid phosphatase (TRAP) staining and PDGF-BB secretion tested by ELISA. In line with decreasing secretion of PDGF-BB by preosteoclasts exposed to zoledronate, conditioned medium (CM) from the cells significantly induced less migration of endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs) compared to CM from unexposed preosteoclasts. Meanwhile, angiogenic function of EPCs and osteoblastic differentiation of MSCs also declined when culturing with CM from preosteoclasts treated by zoledronate (PZ-CM), evidenced by tube formation assay of EPCs and alkaline phosphatase activity of MSCs. Western blot assay showed that the expression of VEGF in EPCs and OCN, RUNX2 in MSCs declined when culturing with PZ-CM compared to CM from preostoeclasts without exposure of zoledronate. Conclusion Our study found that zoledronate was able to suppress preosteoclasts releasing PDGF-BB, resulting in suppression of angiogenesis and osteogenesis. Our study may partly contributed to the mechanism of BRONJ.