Scientific Reports · 6 authors, 4 centres
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This study in bile duct-ligated (BDL) rats, a model of hepatic osteodystrophy, found that naltrexone (NTX) reduced elevated bone thrombospondin-1 (THBS-1) mRNA and increased nitric oxide (NO) levels, suggesting a molecular mechanism for its bone-protective effects. NTX also decreased hepatic collagen deposition, confirming its anti-cirrhotic action. These findings indicate that NTX may partly counteract osteoporosis in chronic liver disease by modulating the THBS1/eNOS/NO pathway.
**Background:** Hepatic osteodystrophy (HO) is a metabolic bone disease in patients with chronic liver disease, characterized by increased bone resorption. Thrombospondin-1 (THBS-1), an extracellular matrix glycoprotein, promotes osteoclast differentiation by inhibiting endothelial nitric oxide synthase (eNOS) activity and nitric oxide (NO) signaling. Naltrexone (NTX), an opioid receptor modulator, has shown anti-cirrhotic and bone-protective effects in previous studies. This study aimed to evaluate the effect of NTX on the THBS1/eNOS/NO pathway in the bones of bile duct-ligated (BDL) rats, a model of HO.
**Methods:** Fifty male Wistar rats were randomly assigned to five groups (n=10 each): controls, sham-operated + normal saline, BDL + normal saline, sham-operated + NTX (10 mg/kg), and BDL + NTX (10 mg/kg). BDL surgery was performed to induce hepatic fibrosis and osteoporosis. After 4 weeks of daily intravenous injections, liver tissues were assessed for collagen deposition (Masson trichrome staining), and left tibiae were analyzed for histomorphometric parameters (cortical thickness/area, trabecular thickness/number) using H&E staining. Radiographic bone density was measured via optical density (OD) on cephalometric radiographs. Right femurs were used for real-time PCR quantification of THBS-1 and eNOS mRNA expression (normalized to β-actin), and for measurement of NO levels using a commercial kit. Statistical analysis was performed using one-way ANOVA with Tukey post-hoc test (p<0.05).
**Key Results:** BDL surgery significantly increased hepatic collagen deposition (p=0.0004), which was significantly reduced by NTX treatment (BDL+NTX vs. BDL+saline). BDL also significantly decreased cortical bone thickness (p=0.0026), cortical bone area (p=0.02), trabecular bone thickness (p=0.018), and trabecular bone number (p<0.001) compared to sham-operated animals. NTX did not induce significant changes in these histomorphometric parameters. Radiographic bone density showed no significant differences among groups. THBS-1 mRNA expression in bone was significantly increased in the BDL group compared to controls (p=0.0025), and this elevation was significantly attenuated by NTX (p=0.012). eNOS mRNA levels were not significantly different across groups. Bone NO levels were significantly decreased in the BDL group compared to sham-operated animals (p=0.012), and this decrease was significantly reversed by NTX administration (p=0.039).
**Clinical Implications:** This study provides evidence that NTX may partially counteract bone loss in hepatic osteodystrophy by reducing THBS-1 expression and restoring NO levels in bone tissue. The findings suggest a novel molecular mechanism involving the THBS1/eNOS/NO pathway through which NTX exerts its bone-protective effects. However, the lack of significant improvement in histomorphometric parameters indicates that longer treatment duration or higher doses may be needed to translate molecular changes into structural bone improvements. These results support further investigation of NTX as a potential therapeutic agent for osteoporosis in patients with chronic liver disease, but clinical studies are required to confirm efficacy and safety in humans.