RANKL synthesized by both stromal cells and cancer cells plays a crucial role in osteoclastic bone resorption induced by oral cancer
RANKL synthesized by both stromal cells and cancer cells plays a crucial role in osteoclastic bone resorption induced by oral cancer
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基质细胞和癌细胞合成的RANKL在口腔癌诱导的破骨细胞骨吸收中起着至关重要的作用
DOI：
10.1016/j.ajpath.2013.01.038
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发表时间：
2013
影响因子：
6
通讯作者：
Akira Yamaguchi
中科院分区：
文献类型：
--
作者：
Kiyoshi Sato;Ji-Won Lee;Kei Sakamoto;Tadahiro Iimura;Kou Kayamori;Hisataka Yasuda;Masanobu Shindoh;Masako Ito;Ken Omura;Akira Yamaguchi
口腔癌侵袭性骨质破坏的分子机制尚不清楚。用免疫组织化学方法证实核因子受体激活剂-κB配体(RANKL)阳性的成纤维细胞和癌细胞位于口腔癌的骨侵袭部位。人口腔癌细胞系HSC3和HO-1-N-1在UAMS-32小鼠成骨细胞系中表达RANKL，并刺激RANKL表达。我们分别使用针对小鼠RANKL和人RANKL的物种特异性RANKL抗体来区分由基质细胞和癌细胞合成的RANKL在癌症相关骨吸收中的作用。HSC3和HO-1-N-1细胞条件培养液在小鼠骨髓细胞和UAMS-32细胞共培养中诱导的破骨细胞形成可被抗RANKL抗体所抑制。在异种移植模型中，给予抗小鼠RANKL抗体可显著抑制HSC3诱导的骨破坏。抗小鼠RANKL抗体和抗人RANKL抗体均能抑制HO-1-N-1诱导的骨破坏。注射抗人RANKL抗体可显著抑制人RANKL高表达细胞(HSC3-R2)移植所致的骨破坏。本研究揭示了由基质细胞和癌细胞产生的RANKL参与了口腔癌诱导的破骨细胞性骨吸收。这些结果为了解癌症相关骨破坏的细胞和分子基础以及RANKL抗体(Denosumab)治疗的作用机制提供了重要信息。
The molecular mechanisms underlying bone destruction by invading oral cancer are not well understood. Using IHC, we demonstrated that receptor activator of nuclear factor-κB ligand (RANKL)–positive fibroblasts and cancer cells were located at sites of bone invasion in human oral cancers. HSC3 and HO-1-N-1, human oral cancer cell lines, expressed RANKL and stimulated Rankl expression in the UAMS-32 murine osteoblastic cell line. We discriminated the roles of RANKL synthesized by stromal cells and cancer cells in cancer-associated bone resorption by using species-specific RANKL antibodies against murine RANKL and human RANKL, respectively. Osteoclastogenesis induced by the conditioned medium of HSC3 and HO-1-N-1 cells in a co-culture of murine bone marrow cells and UAMS-32 cells was inhibited by the addition of antibodies against either mouse or human RANKL. HSC3-induced bone destruction was greatly inhibited by the administration of anti-mouse RANKL antibody in a xenograft model. HO-1-N-1–induced bone destruction was inhibited by the administration of either anti-mouse or anti-human RANKL antibody. Bone destruction induced by the transplantation of humanRANKL-overexpressing cells (HSC3-R2) was greatly inhibited by the injection of anti-human RANKL antibody. The present study revealed that RANKL produced by both stromal and cancer cells is involved in oral cancer–induced osteoclastic bone resorption. These results provide important information for understanding the cellular and molecular basis of cancer-associated bone destruction and the mechanism of action underlying RANKL antibody (denosumab) therapy.