KDM6B-Mediated HADHA Demethylation/Lactylation Regulates Cementogenesis.

Area of Science:

• Biochemistry
• Cell Biology
• Regenerative Medicine

Background:

• Periodontitis causes cementum degeneration and tooth loss, necessitating periodontal regeneration strategies.
• Cementum regeneration is crucial for periodontal regeneration, with cementoblasts and their mineralization being key factors.
• Limited research on cementogenesis highlights the need for novel therapeutic targets.

Purpose of the Study:

• To investigate the role of lysine (K)-specific demethylase 6B (KDM6B) in cementoblast mineralization.
• To elucidate the molecular mechanisms by which KDM6B regulates cementogenesis, focusing on fatty acid oxidation (FAO) and the KDM6B-Hadha axis.
• To explore the potential of KDM6B as a therapeutic target for periodontal regeneration.

Main Methods:

• Quantitative polymerase chain reaction, Western blot, immunofluorescence, and immunohistochemistry were used to detect gene and protein expression.
• In vivo studies using GSK-J4 in mice assessed KDM6B's influence on cementum formation.
• Chromatin immunoprecipitation sequencing, RNA sequencing, and coimmunoprecipitation identified the KDM6B-Hadha axis and HADHA lactylation sites.

Main Results:

• KDM6B and FAO expression increased during cementoblast mineralization.
• KDM6B directly targeted and activated Hadha transcription, upregulating FAO and promoting mineralization.
• KDM6B regulated HADHA lactylation, further enhancing FAO and mineralization; Hadha overexpression or lactate addition rescued KDM6B knockdown-induced inhibition.

Conclusions:

• KDM6B plays a critical role in promoting cementoblast mineralization by upregulating FAO.
• The KDM6B-Hadha axis, involving histone demethylation and HADHA lactylation, is a key pathway in regulating FAO and cementogenesis.
• Targeting KDM6B presents a promising therapeutic strategy for enhancing periodontal regeneration.