Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5940111 | The American Journal of Pathology | 2010 | 13 Pages |
Abstract
We investigated the roles of interleukin-6 (IL-6) and parathyroid hormone-related peptide (PTHrP) in oral squamous cell carcinoma (OSCC)-induced osteoclast formation. Microarray analyses performed on 43 human OSCC specimens revealed that many of the specimens overexpressed PTHrP mRNA, but a few overexpressed IL-6 mRNA. Immunohistochemical analysis revealed that IL-6 was expressed not only in cancer cells but also in fibroblasts and osteoclasts at the tumor-bone interface. Many of the IL-6-positive cells coexpressed vimentin. Conditioned medium (CM) derived from the culture of oral cancer cell lines (BHY, Ca9-22, HSC3, and HO1-u-1) stimulated Rankl expression in stromal cells and osteoclast formation. Antibodies against both human PTHrP and mouse IL-6 receptor suppressed Rankl in ST2 cells and osteoclast formation induced by CM from BHY and Ca9-22, although the inhibitory effects of IL6 antibody were greater than those of PTHrP antibody. CM derived from all of the OSCC cell lines effectively induced IL-6 expression in stromal cells, and the induction was partially blocked by anti-PTHrP antibody. Xenografts of HSC3 cells onto the periosteal region of the parietal bone in athymic mice presented histology and expression profiles of RANKL and IL-6 similar to those observed in bone-invasive human OSCC specimens. These results indicate that OSCC provides a suitable microenvironment for osteoclast formation not only by producing IL-6 and PTHrP but also by stimulating stromal cells to synthesize IL-6.
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Authors
Kou Kayamori, Kei Sakamoto, Tomoki Nakashima, Hiroshi Takayanagi, Kei-ichi Morita, Ken Omura, Su Tien Nguyen, Yoshio Miki, Tadahiro Iimura, Akiko Himeno, Takumi Akashi, Hisafumi Yamada-Okabe, Etsuro Ogata, Akira Yamaguchi,