title: HIF-2 Inhibition Supresses Inflammatory Responses and Osteoclastic Differentiation in Human Periodontal Ligament Cells.
abstract: Recent reports suggest that hypoxia inducible factor-2α (HIF-2α) is a key regulator of osteoarthritis cartilage destruction. However, the precise role of HIF-2α in the inflammatory response and osteoclast differentiation remains unclear. The purpose of this study was to investigate the effect of HIF-2α on inflammatory cytokines, extracellular matrix (ECM) destruction enzymes, and osteoclastic differentiation in nicotine and lipopolysaccharide (LPS)-stimulated human periodontal ligament cells (PDLCs). HIF-2α was upregulated in chronically inflamed PDLCs of periodontitis patients, and in nicotine- and LPS-exposed PDLC in dose- and time-dependent manners. HIF-2α inhibitor and HIF-2α siRNA attenuated the nicotine- and LPS- induced production of NO and PGE2 , upregulation of iNOS, COX-2, pro-inflammatory cytokines (IL-1β, TNF-α, IL-1β, IL-6, IL-8, IL-10, IL-11, and IL-17), and matrix metalloproteinases (MMPs; MMP-1, -8, -13, -2 and -9), and reversed the effect on TIMPs (TIMP-1 and -2) in PDLCs. The conditioned medium produced by nicotine and LPS-treated PDLCs increased the number of TRAP-stained osteoclasts, TRAP activity and osteoclast-specific genes, which has been blocked by HIF-2α inhibition and silencing. HIF-2α inhibitor and HIF-2α siRNA inhibited the effects of nicotine and LPS on the activation of Akt, JAK2 and STAT3, ERK and JNK MAPK, nuclear factor-κB, c-Jun, and c-Fos. Taken together, this study is the first to demonstrate that HIF-2α inhibition exhibits anti-inflammatory activity through the inhibition of inflammatory cytokines and impairment of ECM destruction, as well as blocking of osteoclastic differentiation in a nicotine- and periodontopathogen-stimulated PDLCs model. Thus, HIF-2α inhibition may be a novel molecular target for therapeutic approaches in periodontitis.
authors.affiliation: Department of Oral and Maxillofacial Pathology, Research Center for Tooth and Periodontal Regeneration (MRC), School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Won-Jung
authors.initials: WJ
authors.lastname: Bae
authors.affiliation: Department of Prosthodontics, Dongatn Sacred Heart Hospital, Hallym University, Dongtan, South Korea.
authors.forename: Mee-Ran
authors.initials: MR
authors.lastname: Shin
authors.affiliation: Department of Oral Medicine, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Soo-Kyung
authors.initials: SK
authors.lastname: Kang
authors.affiliation: Department of Oral and Maxillofacial Pathology, Research Center for Tooth and Periodontal Regeneration (MRC), School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
authors.lastname: Zhang-Jun
authors.affiliation: Department of Oral and Maxillofacial Pathology, Research Center for Tooth and Periodontal Regeneration (MRC), School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Jun-Yeol
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Maxillofacial Biomedical Engineering, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Sang-Cheon
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Department of Oral and Maxillofacial Pathology, Research Center for Tooth and Periodontal Regeneration (MRC), School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Eun-Cheol
authors.initials: EC
authors.lastname: Kim
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D009538:Nicotine / Q000494:pharmacology; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010513:Periodontal Ligament / Q000166:cytology / Q000473:pathology*; D010518:Periodontitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D017077:Culture Media, Conditioned; D008070:Lipopolysaccharides; D009538:Nicotine; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C485502:HIF-2 protein, mouse
keywords: HIF-2α; INFLAMMATORY CYTOKINE; OSTEOCLAST; PERIODONTAL LIGAMENT CELLS; PERIODONTITIS