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

Table 1 Comparison of oral-derived stem cell subtypes for osteogenic applications

ODSC type	Osteogenic potential	Key features	Clinical application scenarios	Ref.
DPSCs	High	Forms bone-like structures, suitable for pulp and alveolar repair	Dental pulp regeneration, calvarial and alveolar bone defects	[8,9,18]
GMSCs	Very high	High ALP activity, strong anti-inflammatory and antioxidant capacity	Periodontitis and chronic inflammatory environments	[5,13]
PDLSCs	Moderate	Responsive to gene modification, secretes paracrine factors	Periodontal regeneration, alveolar ridge restoration	[11,12,15]
SHEDs	High	Fast proliferation, suitable for pediatric regenerative applications	Tooth socket preservation, pediatric bone regeneration	[10]
DFPCs	High	Differentiates into osteoblasts, cementoblasts; important for root development	Tooth root and periodontal tissue engineering	[14,16]

ODSC: Oral-derived stem cell; DPSCs: Dental pulp stem cells; GMSCs: Gingiva-derived mesenchymal stem cells; PDLSCs: Periodontal ligament stem cells; SHEDs: Stem cells from human exfoliated deciduous teeth; DFPCs: Dental follicle progenitor cells; ALP: Alkaline phosphatase.

Table 2 Post-translational modification-mediated crosstalk mechanisms in osteogenic signaling

PTM type	Molecular target	Pathway interaction	Functional consequence	Ref.
Acetylation	β-catenin (Lys49)	Wnt-BMP synergy	Enhanced β-catenin/SMAD1 complex stability	[33,37-39]
Methylation	SMAD4 (Arg37)	BMP-Wnt-PI3K integration	Facilitated β-catenin nuclear translocation	[41-43]
Lactylation	H3K18 histone mark	Metabolic-epigenetic coupling	Chromatin priming at osteogenic loci	[44,46,47]
Phosphorylation	GSK3β (Ser9)	PI3K-Wnt crosstalk	β-catenin stabilization	[35,36]
Ubiquitination	SMAD1 (Lys519)	BMP-TGFβ balance	Regulation of SMAD1/2/3 stoichiometry	[52,53]

PTM: Post-translational modification; GSK3β: Glycogen synthase kinase 3 beta; BMP: Bone morphogenetic protein; PI3K: Phosphatidylinositol 3-kinase; TGF: Transforming growth factor.

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.