Maekawa T, Kulwattanaporn P, Hosur K, Domon H, Oda M, Terao Y, Maeda T, Hajishengallis G
1 Graduate School of Medical and Dental Sciences, Research Center for Advanced Oral Science, Niigata University, Niigata, Japan.
2 Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
J Dent Res. 2017 May;96(5):571-577. doi: 10.1177/0022034516687248. Epub 2017 Jan 17.
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.
无翅/整合酶-1（Wnt）蛋白配体家族及其功能性拮抗剂——分泌型卷曲相关蛋白（sFRP），调节着从胚胎发育到免疫和炎症等各种生物学过程。Wnt5a和sFRP5构成了典型的配体/拮抗剂对，并且最近在人类牙周炎中检测到前一种分子的信使核糖核酸（mRNA）水平。本研究的主要目的是调查Wnt5a和sFRP5在人类牙周炎（与健康状态相比）中的表达相互关系，并确定它们在动物模型的炎症和骨质流失中的作用。我们在人类牙龈中检测到了Wnt5a和sFRP5的mRNA，在患病组织中Wnt5a占主导，而在健康组织中sFRP5占主导。Wnt5a和sFRP5蛋白在牙龈上皮中共定位，提示上皮细胞表达，这在培养的人类牙龈上皮细胞（HGEC）中得到了证实。Wnt5a和sFRP5在HGEC中的表达受到促炎刺激（牙龈卟啉单胞菌的脂多糖[LPS]）的差异调节，其方式与临床观察结果一致（即LPS上调Wnt5a而下调sFRP5）。在HGEC中，通过白细胞介素8的产生监测发现，外源性添加的Wnt5a增强了而sFRP5抑制了LPS诱导的炎症。与此一致的是，在结扎诱导的牙周炎小鼠中局部用sFRP5治疗可抑制炎症和骨质流失，这与骨组织切片中破骨细胞数量减少相关。与人类情况一样，小鼠牙周炎与Wnt5a的高表达和sFRP5的低表达相关，尽管在用sFRP5治疗后这种情况发生了逆转。总之，我们证明了在牙周健康和疾病中sFRP5与Wnt5a表达之间存在一种新的相互关系，为将Wnt5a/sFRP5比值用作牙周炎生物标志物的可能性的临床研究铺平了道路。此外，我们表明sFRP5可阻断实验性牙周炎症和骨质流失，这表明其有望成为牙周炎新的宿主调节疗法开发的平台。
