Zoledronic Acid Regulates Osteoclasts via miR-483-5p in the BRONJ

Objectives: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe complication of bisphosphonate therapy, with unclear mechanisms. This study investigates the regulatory impact of zoledronic acid (ZOL) on osteoclasts and microRNA (miRNA) expression.

Materials and methods: Raw264.7 cells and bone marrow-derived macrophages (BMMs) were used to assess ZOL's effects on proliferation and apoptosis. miRNA array analysis was performed during osteoclastogenesis with ZOL treatment. The role of miR-483-5p was examined using miR-mimics and miR-inhibitors. A rat BRONJ model was established for in vivo validation.

Results: A concentration of 2 μM ZOL, which did not affect cell proliferation or apoptosis, was used in subsequent experiments. ZOL altered the expression of 64 miRNAs (39 upregulated, 25 downregulated). miR-483-5p mimics alleviated ZOL-induced inhibition of osteoclastogenesis, actin ring formation, bone resorption, and differentiation marker expression, whereas inhibitors enhanced these effects. In vivo, Ago-miR-483-5p promoted wound healing in the BRONJ model, while Antago-miR-483-5p impaired it.

Conclusions: ZOL modulates osteoclast function in BRONJ through miR-483-5p inhibition. miR-483-5p may serve as a novel therapeutic target for BRONJ treatment, providing new insights into managing this complication.