title: The Role of Sonic Hedgehog Signaling in Osteoclastogenesis and Jaw Bone Destruction.
abstract: Sonic hedgehog (SHH) and its signaling have been identified in several human cancers, and increased levels of its expression appear to correlate with disease progression and metastasis. However, the role of SHH in bone destruction associated with oral squamous cell carcinomas is still unclear. In this study we analyzed SHH expression and the role played by SHH signaling in gingival carcinoma-induced jawbone destruction. From an analysis of surgically resected lower gingival squamous cell carcinoma mandible samples, we found that SHH was highly expressed in tumor cells that had invaded the bone matrix. On the other hand, the hedgehog receptor Patched and the signaling molecule Gli-2 were highly expressed in the osteoclasts and the progenitor cells. SHH stimulated osteoclast formation and pit formation in the presence of the receptor activator for nuclear factor-κB ligand (RANKL) in CD11b+ mouse bone marrow cells. SHH upregulated phosphorylation of ERK1/2 and p38 MAPK, NFATc1, tartrate-resistant acid phosphatase (TRAP), and Cathepsin K expression in RAW264.7 cells. Our results suggest that tumor-derived SHH stimulated the osteoclast formation and bone resorption in the tumor jawbone microenvironment.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shimo
authors.affiliation: Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, Japan.
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Takabatake
authors.affiliation: Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Aoyama
authors.affiliation: Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Takebe
authors.affiliation: Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Ibaragi
authors.affiliation: Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Okui
authors.affiliation: Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, Japan.
authors.forename: Naito
authors.initials: N
authors.lastname: Kurio
authors.affiliation: Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takada
authors.affiliation: Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, Japan.
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Obata
authors.affiliation: Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, Japan.
authors.forename: Pai
authors.initials: P
authors.lastname: Pang
authors.affiliation: Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Iwamoto
authors.affiliation: Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nagatsuka
authors.affiliation: Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Sasaki
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000503:physiopathology*; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D008339:Mandibular Neoplasms / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D010010:Osteoclasts / Q000166:cytology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D053823:Hedgehog Proteins; C509239:SHH protein, human