title: PIN1 inhibition suppresses osteoclast differentiation and inflammatory responses.
abstract: Inflammatory responses and osteoclast differentiation play pivotal roles in the pathogenesis of osteolytic bone diseases such as periodontitis. Although overexpression or inhibition of peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (PIN1) offers a possible therapeutic strategy for chronic inflammatory diseases, the role of PIN1 in periodontal disease is unclear. The aim of the present study was to evaluate PIN1 expression in periodontitis patients as well as the effects of PIN1 inhibition by juglone or PIN1 small-interfering RNA (siRNA) and of PIN1 overexpression using a recombinant adenovirus encoding PIN1 (Ad-PIN1) on the inflammatory response and osteoclastic differentiation in lipopolysaccharide (LPS)- and nicotine-stimulated human periodontal ligament cells (PDLCs). PIN1 was up-regulated in chronically inflamed PDLCs from periodontitis patients and in LPS- and nicotine-exposed PDLCs. Inhibition of PIN1 by juglone or knockdown of PIN1 gene expression by siRNA markedly attenuated LPS- and nicotine-stimulated prostaglandin E2 (PGE2) and nitric oxide (NO) production, as well as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, whereas PIN1 overexpression by Ad-PIN1 increased it. LPS- and nicotine-induced nuclear factor (NF)-κB activation was blocked by juglone and PIN1 siRNA but increased by Ad-PIN1. Conditioned medium prepared from LPS- and nicotine-treated PDLCs increased the number of tartrate-resistant acid phosphatase-stained osteoclasts and osteoclast-specific gene expression. These responses were blocked by PIN1 inhibition and silencing but stimulated by Ad-PIN1. Furthermore, juglone and PIN1 siRNA inhibited LPS- and nicotine-induced osteoclastogenic cytokine expression in PDLCs. This study is the first to demonstrate that PIN1 inhibition exhibits anti-inflammatory effects and blocks osteoclastic differentiation in LPS- and nicotine-treated PDLCs. PIN1 inhibition may be a therapeutic strategy for inflammatory osteolysis in periodontal disease.
authors.affiliation: Department of Oral and Maxillofacial Pathology, Research Center for Tooth and Periodontal Regeneration (MRC), School of Dentistry and Institute of Oral Biology, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Y-A
authors.initials: YA
authors.lastname: Cho
authors.affiliation: Department of Oral Anatomy and Developmental Biology, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: S-S
authors.initials: SS
authors.lastname: Jue
authors.affiliation: Department of Oral and Maxillofacial Pathology, Research Center for Tooth and Periodontal Regeneration (MRC), School of Dentistry and Institute of Oral Biology, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: W-J
authors.initials: WJ
authors.lastname: Bae
authors.affiliation: Department of Oral and Maxillofacial Pathology, Research Center for Tooth and Periodontal Regeneration (MRC), School of Dentistry and Institute of Oral Biology, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: S-H
authors.initials: SH
authors.lastname: Heo
authors.affiliation: Department of Periodontology, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: S-I
authors.initials: SI
authors.lastname: Shin
authors.affiliation: Department of Maxillofacial Biomedical Engineering, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: I-K
authors.initials: IK
authors.lastname: Kwon
authors.affiliation: Department of Maxillofacial Biomedical Engineering, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: S-C
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 and Institute of Oral Biology, Kyung Hee University, Seoul, Republic of Korea eckim@khu.ac.kr.
authors.forename: E-C
authors.initials: EC
authors.lastname: Kim
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects; D017077:Culture Media, Conditioned; D051546:Cyclooxygenase 2 / Q000032:analysis; D015232:Dinoprostone / Q000032:analysis; D005260:Female; D055785:Gene Knockdown Techniques; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008070:Lipopolysaccharides / Q000009:adverse effects; D008297:Male; D008813:Mice, Inbred ICR; D008875:Middle Aged; D016328:NF-kappa B / Q000032:analysis; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones / Q000494:pharmacology; D009538:Nicotine / Q000009:adverse effects; D009569:Nitric Oxide / Q000032:analysis; D052247:Nitric Oxide Synthase Type II / Q000032:analysis; D010010:Osteoclasts / Q000187:drug effects*; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors* / Q000235:genetics; D010513:Periodontal Ligament / Q000187:drug effects / Q000473:pathology; D010518:Periodontitis / Q000201:enzymology*; D034741:RNA, Small Interfering / Q000235:genetics; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D017077:Culture Media, Conditioned; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones; D034741:RNA, Small Interfering; D009569:Nitric Oxide; D009538:Nicotine; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse; D015232:Dinoprostone; C005134:juglone
keywords: Pin1 peptidylprolyl isomerase; antiinflammatory agents; lipopolysaccharides; nicotine; osteoclasts; periodontitis