2. Academic Validation
  3. Rescuing Mitochondrial Dysfunction in Macrophages Prevents Osteonecrosis of the Jaw in Anti-Resorptive Therapy

Rescuing Mitochondrial Dysfunction in Macrophages Prevents Osteonecrosis of the Jaw in Anti-Resorptive Therapy

  • Adv Sci (Weinh). 2025 Dec 7:e17586. doi: 10.1002/advs.202517586.
Hang Zhang 1 2 3,  Xin Shen 1 2 3,  Haiyang Liu 1 2,  Xinxi Yuan 1 2,  Mumin Cao 4,  Xuepeng Lv 5,  Ziji Ling 1 2 3,  Songsong Guo 1 2,  Rongyao Xu 1 2 3,  Xiang Li 1 2 3,  Hongbing Jiang 1 2 3
Affiliations

Affiliations

  • 1 State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, 210029, China.
  • 2 Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, 210029, China.
  • 3 Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, 210029, China.
  • 4 Department of Orthopaedics, Orthopaedic Trauma Institute (OTI), Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China.
  • 5 State Key Lab of Digital Medical Engineering, Jiangsu Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 211189, China.
PMID: 41354629 DOI: 10.1002/advs.202517586
Abstract

Mitochondria-driven macrophage dysregulation contributes significantly to inflammatory disease progression; however, the mechanism underlying bisphosphonate-related osteonecrosis of the jaw (BRONJ) remains unclear. This study demonstrates that zoledronic acid (ZA) disrupts mitochondrial bioenergetic function in macrophages, leading to elevated mitochondrial membrane potential, excessive mitochondrial Reactive Oxygen Species (mtROS), and increased HIF-1α expression, which together promote a pro-inflammatory transition in macrophages. ZA further inhibits Autophagy by activating the TLR4-MyD88/PI3K-AKT-mTOR pathway, preventing the clearance of dysfunctional mitochondria and sustaining superoxide production. Genetic loss of Atg5 in innate immune cells disrupts autophagosome maturation and markedly worsens ZA-induced BRONJ development. To restore mitochondrial degradation and biofunction, ZA-loaded nanoparticles incorporating the mTOR Inhibitor rapamycin (ZDPR) are developed. ZDPR effectively prevents BRONJ and exerts therapeutic benefits in osteoporosis and osteolysis. These findings highlight bone-targeted mitochondria rescue as a promising strategy to enhance antiresorptive therapy.

Keywords

PI3K‐AKT‐mTOR pathway; anti‐resorptive therapy; autophagy; bisphosphonate‐related osteonecrosis of the jaw; macrophage polarization; mitochondrial dysfunction; zoledronic acid.

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