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HIF‐2 Inhibition Supresses Inflammatory Responses and Osteoclastic Differentiation in Human Periodontal Ligament Cells

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. J. Cell. Biochem. 116: 1241–1255, 2015. © 2015 Wiley Periodicals, Inc.