2. Academic Validation
  3. Menaquinone-4 prevents medication-related osteonecrosis of the jaw through the SIRT1 signaling-mediated inhibition of cellular metabolic stresses-induced osteoblast apoptosis

Menaquinone-4 prevents medication-related osteonecrosis of the jaw through the SIRT1 signaling-mediated inhibition of cellular metabolic stresses-induced osteoblast apoptosis

  • Free Radic Biol Med. 2023 Sep:206:33-49. doi: 10.1016/j.freeradbiomed.2023.06.022.
Yajun Cui 1,  Weidong Zhang 1,  Panpan Yang 2,  Siqi Zhu 3,  Shenglei Luo 4,  Minqi Li 5
Affiliations

Affiliations

  • 1 Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, China; Center of Osteoporosis and Bone Mineral Research, Shandong University, China.
  • 2 Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Road, 250021, Jinan, China.
  • 3 Center of Osteoporosis and Bone Mineral Research, Shandong University, China; The Second Affiliated Hospital of Jinzhou Medical University, Jinzhou, China.
  • 4 Department of Oral and Maxillofacial Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, 250033, 247 Beiyuan Street, Jinan, Shandong, China. Electronic address: [email protected].
  • 5 Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, China; Center of Osteoporosis and Bone Mineral Research, Shandong University, China. Electronic address: [email protected].
PMID: 37364692 DOI: 10.1016/j.freeradbiomed.2023.06.022
Abstract

Long-term usage of bisphosphonates, especially zoledronic acid (ZA), induces osteogenesis disorders and medication-related osteonecrosis of the jaw (MRONJ) in patients, thereby contributing to the destruction of bone remodeling and the continuous progression of osteonecrosis. Menaquinone-4 (MK-4), a specific vitamin K2 isoform converted by the mevalonate (MVA) pathway in vivo, exerts the promotion of bone formation, whereas ZA administration suppresses this pathway and results in endogenous MK-4 deficiency. However, no study has evaluated whether exogenous MK-4 supplementation can prevent ZA-induced MRONJ. Here we showed that MK-4 pretreatment partially ameliorated mucosal nonunion and bone sequestration among ZA-treated MRONJ mouse models. Moreover, MK-4 promoted bone regeneration and inhibited osteoblast Apoptosis in vivo. Consistently, MK-4 downregulated ZA-induced osteoblast Apoptosis in MC3T3-E1 cells and suppressed the levels of cellular metabolic stresses, including oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and DNA damage, which were accompanied by elevated Sirtuin 1 (SIRT1) expression. Notably, EX527, an inhibitor of the SIRT1 signaling pathway, abolished the inhibitory effects of MK-4 on ZA-induced cell metabolic stresses and osteoblast damage. Combined with experimental evidences from MRONJ mouse models and MC3T3-E1 cells, our findings suggested that MK-4 prevents ZA-induced MRONJ by inhibiting osteoblast Apoptosis through suppression of cellular metabolic stresses in a SIRT1-dependent manner. The results provide a novel translational direction for the clinical application of MK-4 for preventing MRONJ.

Keywords

MRONJ; Menaquinone-4; Mitochondrial dysfunction; Oxidative stress; SIRT1; Zoledronate acid.

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