Hypoxic dental pulp stem cells-released succinate promotes osteoclastogenesis and root resorption

Area of Science:

• Cell Biology
• Stem Cell Research
• Orthodontics
• Biochemistry

Background:

• Endodontically-treated teeth show reduced root resorption during orthodontic movement.
• Orthodontically induced inflammatory root resorption (OIIRR) is a complex biological process.
• The role of dental pulp stem cells (DPSCs) and their metabolic byproducts in OIIRR requires further investigation.

Purpose of the Study:

• To investigate whether hypoxic dental pulp stem cells (DPSCs) promote osteoclastogenesis.
• To explore the role of succinate, a metabolite of hypoxic DPSCs, in OIIRR.
• To elucidate the mechanism involving the succinate-SUCNR1 axis in osteoclast differentiation and root resorption.

Main Methods:

• Quantification of succinate in DPSC supernatant under normoxic and hypoxic conditions.
• Culture of bone marrow-derived macrophages (BMDMs) with conditioned medium from hypoxic DPSCs (Hypo-CM), exogenous succinate, or SUCNR1 inhibitor (4c).
• Assessment of osteoclastogenesis using TRAP staining, Transwell assays, qPCR, Western blotting, and resorption assays in wild-type and SUCNR1-knockout mice.

Main Results:

• Hypoxic DPSCs released significantly higher concentrations of succinate.
• Hypo-CM and exogenous succinate promoted M1 macrophage polarization and osteoclast differentiation, evidenced by increased TRAP and NFATc1 expression.
• SUCNR1 knockout in BMDMs significantly inhibited macrophage migration, M1 polarization, osteoclastogenesis, and cementum resorption.

Conclusions:

• DPSC-derived succinate under hypoxic conditions promotes osteoclast differentiation and exacerbates root resorption.
• The succinate-SUCNR1 signaling pathway is a key mediator in OIIRR.
• Targeting the succinate-SUCNR1 axis presents a potential therapeutic strategy to mitigate OIIRR.