Protective and therapeutic effects of gallic acid on medication-related osteonecrosis of the jaw in rats: modulation of inflammation, fibrosis and endoplasmic reticulum/mitochondrial stress pathways.

BACKGROUND: Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse effect of long-term bisphosphonate therapy characterized by impaired bone remodeling, inflammation, and fibrosis. Gallic acid (GA), a natural phenolic compound with potent antioxidant and anti-inflammatory properties, has been proposed as a protective agent against drug-induced tissue injury. This study investigated the prophylactic and therapeutic effects of GA on zoledronic acid (ZOA)–induced MRONJ in rats. METHODS: Thirty-two adult female Wistar albino rats were randomly divided into four groups (n = 8): Control, MRONJ (ZOA + tooth extraction), MRONJ + Pre-GA (prophylactic GA), and MRONJ + Post-GA (therapeutic GA). MRONJ was induced by intraperitoneal ZOA (0.06 mg/kg/week, 5 weeks) followed by mandibular molar extraction. GA (100 mg/kg, i.p.) was administered either before or after ZOA exposure for 7 days. Mandibular tissues were analyzed histopathologically, immunohistochemically (Fibroblast growth factor [FGF], transforming growth factor beta 1 [TGF-1β], tumor necrosis factor alpha [TNF-α]), and molecularly (TNF-α, TGF-1β, endothelial nitric oxide synthase [eNOS], cytochrome c [Cyt-C], caspase-3 [Cas-3], protein kinase RNA-like ER kinase [PERK], C/EBP homologous protein [CHOP]). RESULTS: MRONJ rats exhibited severe osteonecrosis, increased inflammation and fibrosis, disrupted collagen organization, elevated osteoclast activity, and suppressed osteoblast function. Immunohistochemistry revealed significant downregulation of FGF and TGF-1β with a concomitant rise in TNF-α. Gene expression analyses showed upregulation of TNF-α, TGF-1β, CHOP, PERK, Cyt-C, and Cas-3, along with downregulation of eNOS. GA administration markedly ameliorated these alterations, restoring bone architecture, normalizing growth factor expression, suppressing pro-inflammatory and apoptotic signaling, and reducing ER stress. The prophylactic regimen showed the most pronounced protective efficacy. CONCLUSIONS: GA confers both preventive and therapeutic benefits against MRONJ by mitigating oxidative stress, inflammation, fibrosis, ER stress and mitochondrial apoptosis. These findings suggest that GA may represent a promising adjuvant strategy for managing or preventing MRONJ in patients receiving long-term antiresorptive therapy.