The Role of Sonic Hedgehog Signaling in Osteoclastogenesis and Jaw Bone Destruction

• Published in: PloS one Vol. 11; no. 3; p. e0151731
• Main Authors: Shimo, Tsuyoshi, Matsumoto, Kenichi, Takabatake, Kiyofumi, Aoyama, Eriko, Takebe, Yuichiro, Ibaragi, Soichiro, Okui, Tatsuo, Kurio, Naito, Takada, Hiroyuki, Obata, Kyoichi, Pang, Pai, Iwamoto, Masahiro, Nagatsuka, Hitoshi, Sasaki, Akira
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.03.2016; Public Library of Science (PLoS)
• Subjects: Acid phosphatase; Acid phosphatase (tartrate-resistant); Acid resistance; Animals; Biocompatibility; Biology and Life Sciences; Bone growth; Bone marrow; Bone matrix; Bone resorption; Bone surgery; Cancer therapies; Carcinoma, Squamous Cell - pathology; Carcinoma, Squamous Cell - physiopathology; Cathepsin K; CD11b antigen; Cell Differentiation - physiology; Cell Line; Cell Proliferation; Cells (biology); Cellular signal transduction; Dentistry; Destruction; Growth factors; Hedgehog protein; Hedgehog Proteins - physiology; Humans; Jaw; Jawbone; Kinases; Mandible; Mandibular Neoplasms - pathology; Mandibular Neoplasms - physiopathology; MAP kinase; Maxillofacial surgery; Medical prognosis; Medicine; Medicine and Health Sciences; Metastases; Metastasis; Mice; Oral carcinoma; Oral squamous cell carcinoma; Osteoclastogenesis; Osteoclasts; Osteoclasts (Biology); Osteoclasts - cytology; Osteogenesis; Osteoprogenitor cells; Pathology; Patients; Pharmaceutical sciences; Phosphorylation; Proteins; Signal Transduction - physiology; Signaling; Sonic hedgehog; Squamous cell carcinoma; TRANCE protein; Tumor cells; Tumors; University graduates; United States > US; Japan; Pennsylvania
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0151731

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.