RNA-seq analyses of human periodontal ligament fibroblasts (PDLF) stimulated with GNE495 and FGF-2

ABSTRACT: Once periodontal structures are lost, periodontitis becomes difficult to reverse. Herein, the use of GNE-495 to pharmacologically inhibit MAP4K4 was evaluated to promote regeneration via the proliferation of periodontal ligament fibroblasts (PDLFs). The augmentation of this process by fibroblast growth factor-2 (FGF-2) was also assessed. Although FGF-2 has a precedent in clinical use, its benefits alone were modest. This motivated a complementary strategy with MAP4K4 blockade. Human PDLFs were assayed for proliferation and osteogenic capacity in vitro, and a murine ligature model tested local drug delivery during the regeneration phase. Outcomes included cementoenamel junction–alveolar bone crest (CEJ–ABC) distance and bone volume fraction. Transcriptome and protein analyses probed the mechanisms of action using the SREBP inhibitor PF-429242 with cyclin D1 (CCND1) readouts. GNE-495 increased PDLF proliferation without loss of mineralization. In mice, GNE-495 accelerated periodontal tissue regeneration. FGF-2 co-administration produced greater regeneration than either agent alone. In vitro, FGF-2 modestly accelerated early proliferation but reduced alkaline phosphatase (ALP). Combined with GNE-495, it produced a sustained proliferative gain, which is consistent with an immature, pro-regenerative phenotype. RNA sequencing revealed the enrichment of lipid metabolic programs and SREBP1 signaling with GNE-495, which was potentiated by FGF-2. SREBP1 protein levels increased with GNE-495 ± FGF-2, and SREBP blockade reduced proliferation and CCND1 induction. Local MAP4K4 inhibition promotes PDLF proliferation and periodontal tissue regeneration, and FGF-2 amplifies these benefits synergistically. Targeting MAP4K4 alone or with FGF-2 emerges as a promising strategy for periodontal regeneration by engaging an SREBP1-CCND1-linked lipid metabolic program.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313228 | GEO | 2026/09/15

REPOSITORIES: GEO