# 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

## TL;DR

Gallic acid helps prevent and treat a severe jaw condition caused by long-term medication, by reducing inflammation, tissue damage, and stress in rats.

## Contribution

Gallic acid shows both preventive and therapeutic efficacy against medication-related osteonecrosis of the jaw in a rat model.

## Key findings

- Gallic acid reduced inflammation, fibrosis, and stress markers in rats with medication-induced jaw damage.
- Prophylactic gallic acid administration showed stronger protective effects than therapeutic use.
- Gallic acid restored bone structure and normalized growth factor expression in affected rats.

## Abstract

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.

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]).

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.

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.