title: Demethylation of IGFBP5 by Histone Demethylase KDM6B Promotes Mesenchymal Stem Cell-Mediated Periodontal Tissue Regeneration by Enhancing Osteogenic Differentiation and Anti-Inflammation Potentials.
abstract: Mesenchymal stem cell (MSC)-mediated periodontal tissue regeneration is considered a promising method for periodontitis treatment. The molecular mechanism underlying directed differentiation and anti-inflammatory actions remains unclear, thus limiting potential MSC application. We previously found that insulin-like growth factor binding protein 5 (IGFBP5) is highly expressed in dental tissue-derived MSCs compared with in non-dental tissue-derived MSCs. IGFBP5 is mainly involved in regulating biological activity of insulin-like growth factors, and its functions in human MSCs and tissue regeneration are unclear. In this study, we performed gain- and loss-of-function assays to test whether IGFBP5 could regulate the osteogenic differentiation and anti-inflammatory potential in MSCs. We found that IGFBP5 expression was upregulated upon osteogenic induction, and that IGFBP5 enhanced osteogenic differentiation in MSCs. We further showed that IGFBP5 prompted the anti-inflammation effect of MSCs via negative regulation of NFκB signaling. Depletion of the histone demethylase lysine (K)-specific demethylase 6B (KDM6B) downregulated IGFBP5 expression by increasing histone K27 methylation in the IGFBP5 promoter. Moreover, IGFBP5 expression in periodontal tissues was downregulated in individuals with periodontitis compared with in healthy people, and IGFBP5 enhanced MSC-mediated periodontal tissue regeneration and alleviated local inflammation in a swine model of periodontitis. In conclusion, our present results reveal a new function for IGFBP5, provide insight into the mechanism underlying the directed differentiation and anti-inflammation capacities of MSCs, and identify a potential target mediator for improving tissue regeneration.
authors.affiliation: Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China.|Department of Endodontics, Tianjin Medical University School of Stomatology, Tianjin, China.|Molecular Laboratory for Gene Therapy and Tooth Regeneration, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China.
authors.forename: Dayong
authors.initials: D
authors.lastname: Liu
authors.affiliation: Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China.|Department of Endodontics, Tianjin Medical University School of Stomatology, Tianjin, China.
authors.forename: Yuejun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Endodontics, Tianjin Medical University School of Stomatology, Tianjin, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.affiliation: Molecular Laboratory for Gene Therapy and Tooth Regeneration, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China.|Department of Biochemistry and Molecular Biology, Capital Medical University School of Basic Medical Sciences, Beijing, China.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Capital Medical University School of Stomatology, Beijing, China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Endodontics, Tianjin Medical University School of Stomatology, Tianjin, China.
authors.forename: Jianqiu
authors.initials: J
authors.lastname: Song
authors.affiliation: Molecular Laboratory for Gene Therapy and Tooth Regeneration, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China.|Department of Biochemistry and Molecular Biology, Capital Medical University School of Basic Medical Sciences, Beijing, China.
authors.forename: Songlin
authors.initials: S
authors.lastname: Wang
authors.affiliation: Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Fan
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004195:Disease Models, Animal; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000235:genetics / Q000378:metabolism*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008745:Methylation; D010012:Osteogenesis; D010518:Periodontitis / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D010519:Periodontium / Q000502:physiology*; D012038:Regeneration; D013552:Swine; D013556:Swine, Miniature
chemical_list: D006657:Histones; D018975:Insulin-Like Growth Factor Binding Protein 5; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human
keywords: Histone demethylase; Inflammation; Insulin-like growth factor binding protein 5; Lysine (K)-specific demethylase 6B; Mesenchymal stem cells; Osteogenic differentiation