Abstract
The periodontal ligament is a soft connective tissue embedded between the alveolar bone and cementum, the surface hard tissue of teeth. Periodontal ligament fibroblasts (PDLF) actively express osteo/cementogenic genes, which contribute to periodontal tissue homeostasis. However, the key factors maintaining the osteo/cementogenic abilities of PDLF remain unclear. We herein demonstrated that PPARγ was expressed by in vivo periodontal ligament tissue and its distribution pattern correlated with alkaline phosphate enzyme activity. The knockdown of PPARγ markedly reduced the osteo/cementogenic abilities of PDLF in vitro, whereas PPARγ agonists exerted the opposite effects. PPARγ was required to maintain the acetylation status of H3K9 and H3K27, active chromatin markers, and the supplementation of acetyl-CoA, a donor of histone acetylation, restored PPARγ knockdown-induced decreases in the osteo/cementogenic abilities of PDLF. An RNA-seq/ChIP-seq combined analysis identified four osteogenic transcripts, RUNX2, SULF2, RCAN2, and RGMA, in the PPARγ-dependent active chromatin region marked by H3K27ac. Furthermore, RUNX2-binding sites were selectively enriched in the PPARγ-dependent active chromatin region. Collectively, these results identified PPARγ as the key transcriptional factor maintaining the osteo/cementogenic abilities of PDLF and revealed that global H3K27ac modifications play a role in the comprehensive osteo/cementogenic transcriptional alterations mediated by PPARγ.
Highlights
Periodontitis is a lifestyle disease that is characterized by the breakdown of periodontal tissues, which comprise the alveolar bone, periodontal ligament tissue, cementum, and gingiva [1]
Despite the lack of evidence to show whether Periodontal ligament fibroblasts (PDLF) alone or PDLF and stem cells contribute to periodontal tissue homeostasis, the pivotal roles of PDLF have been validated by the conditional knockout mice of Wntless under Osteocalcin-cre recombinase [15]
The present study investigated whether alterations in PPARγ activity by Thiazolidinedione compounds (TZDs) and the suppression of endogenous PPARγ expression in PDLF modulates osteogenic and ECM-related gene expression
Summary
Periodontitis is a lifestyle disease that is characterized by the breakdown of periodontal tissues, which comprise the alveolar bone, periodontal ligament tissue, cementum, and gingiva [1]. Even though the diversity of PDLF currently remains unclear, they have been characterized by two major factors: (1) retained ability to differentiate into osteo/cementogenic cells [13], and (2) the aggressive synthesis and secretion of collagen type 1 and the molecules required for collagen fibrillogenesis in order to compensate for the fast turnover of collagen fibers in periodontal tissue, which is essential for maintaining connective attachments [14]. Despite the lack of evidence to show whether PDLF alone or PDLF and stem cells contribute to periodontal tissue homeostasis, the pivotal roles of PDLF have been validated by the conditional knockout mice of Wntless under Osteocalcin-cre recombinase [15]. In the periodontal tissue of conditional knockout mice of Wntless, the periodontal ligament and cementum were wider, the alveolar bone was narrower, and the expression of osteogenic markers, such as Alp, Runx, and Osterix, was downregulated [15].
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