title: Differential Expression and Roles of Secreted Frizzled-Related Protein 5 and the Wingless Homolog Wnt5a in Periodontitis.
abstract: The Wingless/integrase-1 (Wnt) family of protein ligands and their functional antagonists, secreted frizzled-related proteins (sFRPs), regulate various biological processes ranging from embryonic development to immunity and inflammation. Wnt5a and sFRP5 comprise a typical ligand/antagonist pair, and the former molecule was recently detected at the messenger RNA (mRNA) level in human periodontitis. The main objective of this study was to investigate the interrelationship of expression of Wnt5a and sFRP5 in human periodontitis (as compared to health) and to determine their roles in inflammation and bone loss in an animal model. We detected both Wnt5a and sFRP5 mRNA in human gingiva, with Wnt5a dominating in diseased and sFRP5 in healthy tissue. Wnt5a and sFRP5 protein colocalized in the gingival epithelium, suggesting epithelial cell expression, which was confirmed in cultured human gingival epithelial cells (HGECs). The HGEC expression of Wnt5a and sFRP5 was differentially regulated by a proinflammatory stimulus (lipopolysaccharide [LPS] from Porphyromonas gingivalis) in a manner consistent with the clinical observations (i.e., LPS upregulated Wnt5a and downregulated sFRP5). In HGECs, exogenously added Wnt5a enhanced whereas sFRP5 inhibited LPS-induced inflammation, as monitored by interleukin 8 production. Consistent with this, local treatment with sFRP5 in mice subjected to ligature-induced periodontitis inhibited inflammation and bone loss, correlating with decreased numbers of osteoclasts in bone tissue sections. As in humans, mouse periodontitis was associated with high expression of Wnt5a and low expression of sFRP5, although this profile was reversed after treatment with sFRP5. In conclusion, we demonstrated a novel reciprocal relationship between sFRP5 and Wnt5a expression in periodontal health and disease, paving the way to clinical investigation of the possibility of using the Wnt5a/sFRP5 ratio as a periodontitis biomarker. Moreover, we showed that sFRP5 blocks experimental periodontal inflammation and bone loss, suggesting a promising platform for the development of a new host modulation therapy in periodontitis.
authors.affiliation: 1 Graduate School of Medical and Dental Sciences, Research Center for Advanced Oral Science, Niigata University, Niigata, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Maekawa
authors.affiliation: 2 Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.|3 Department of Operative Dentistry, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand.
authors.forename: P
authors.initials: P
authors.lastname: Kulwattanaporn
authors.affiliation: 2 Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Hosur
authors.affiliation: 4 Division of Microbiology and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Domon
authors.affiliation: 4 Division of Microbiology and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.|5 Departmant of Microbiology and Infection Control Science, Kyoto Pharmaceutical University, Yamashina, Kyoto, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Oda
authors.affiliation: 4 Division of Microbiology and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Terao
authors.affiliation: 1 Graduate School of Medical and Dental Sciences, Research Center for Advanced Oral Science, Niigata University, Niigata, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Maeda
authors.affiliation: 2 Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Hajishengallis
mesh_terms: D016301:Alveolar Bone Loss / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005881:Gingiva / Q000166:cytology; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010518:Periodontitis / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D016966:Porphyromonas gingivalis; D012333:RNA, Messenger / Q000378:metabolism; D000071818:Wnt-5a Protein / Q000378:metabolism*; D000099274:Frizzled-Related Proteins
chemical_list: D015415:Biomarkers; D006023:Glycoproteins; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D000071818:Wnt-5a Protein; D000099274:Frizzled-Related Proteins; C085389:WNT5A protein, human
keywords: LPS; Wnt proteins; biomarkers; bone loss; gingival epithelial cells; inflammation