Post-translational modifications in osteogenic differentiation of oral-derived stem cells: Mechanisms and clinical implications

Table 3 Summary of major post-translational modifications in osteogenic differentiation of oral-derived stem cells

PTM type	Mechanism of action	Key molecules/enzymes	Therapeutic implications	Ref.
Phosphorylation	Activates RUNX2, SMADs, CREB via ERK/p38 phosphorylation to initiate osteogenic gene transcription	ERK, p38, CREB, SMAD1/5/8	BMP2 peptides, ERK activators promote differentiation	[19,21,23-25,35,36]
Acetylation	Loosens chromatin via p300/CBP; stabilizes RUNX2; HDAC inhibition enhances transcription	p300, CBP, HDACs, RUNX2	HDAC inhibitors (TSA, VPA), resveratrol support bone formation	[1,31,35,37,38]
Lactylation	Restores gene expression in LPS-inflamed ODSCs; rescues RUNX2, ALP, COL1A1	Histone H3, proanthocyanidins	Natural anti-inflammatory agents restore osteogenesis in disease states	[1,54]
Ubiquitination	Targets RUNX2/SMAD1 for degradation (Smurf1); USP7 reverses this to enhance osteogenesis	Smurf1, USP7, β-catenin	Proteasome or E3 Ligase inhibitors improve cell survival and differentiation	[41,42]
Methylation	Repressive (H3K27me3) and active (H3K4me3) methylation dynamically regulate osteogenic loci	EZH2, KDM6B, H3K27, H3K4	EZH2 inhibitors and demethylase activators restore suppressed osteogenesis	[39,40]
Palmitoylation	BMPR1a palmitoylation by ZDHHC9 boosts SMAD signaling; links lipid metabolism to osteogenesis	ZDHHC9, ZDHHC16, BMPR1a, CREB	Metabolic enhancement and scaffold engineering using palmitoylation pathways	[26,43]
Glycosylation	Glycosylation of receptors, such as BMP and Wnt receptors, modulates ligand binding affinity and receptor internalization, influencing signaling pathways critical for osteogenesis	BMP receptors, Wnt receptors, OGT	Enhancing receptor signaling in osteogenesis; therapeutic strategies for bone regeneration in inflammatory environments	[48,50]

PTM: Post-translational modification; RUNX2: Runt-related transcription factor 2; CREB: CAMP response element-binding protein; ERK: Extracellular signal-regulated kinases; BMP: Bone morphogenetic protein; CBP: CAMP response element-binding protein binding protein; HDAC: Histone deacetylase; TSA: Trichostatin A; VPA: Valproic acid; LPS: Lipopolysaccharide; ODSCs: Oral-derived stem cells; ALP: Alkaline phosphatase; COL1A1: Collagen type I; H3K27me3: Trimethylation of H3 on lysine 27; EZH2: Enhancer of zeste homolog 2; BMPR1a: Bone morphogenetic protein receptor 1a; OGT: O-linked N-acetylglucosamine transferase.