Hepatocyte VDR protects against cirrhosis-associated bone loss via repression of the FN1/Integrin αv signaling.

Abstract

Introduction: Vitamin D and its receptor (VDR) are essential for liver homeostasis and bone development, and their dysfunction has been implicated in cirrhosis-associated osteoporosis.

Objectives: This study aimed to elucidate the molecular mechanisms linking hepatic injury to bone fragility.

Methods: We examined VDR dysfunction in cirrhotic patients and in a murine model of cirrhosis. Hepatocyte-specific VDR knockout mice were used to determine the contribution of hepatic VDR to bone loss during cirrhosis.

Results: Analysis of UK Biobank data, a Chinese patient cohort, and murine cirrhosis models demonstrated that reduced serum 25-hydroxyvitamin D (25-OHD) correlates with hepatic fibroinflammation and low bone mass. However, vitamin D₃ supplementation failed to restore bone density, indicating noncanonical VDR signaling in bone homeostasis. Hepatic VDR expression declined with progressive fibrosis, and hepatocyte-specific VDR deletion exacerbated trabecular bone loss through enhanced osteoclastogenesis without altering bone formation. Mechanistically, VDR deficiency upregulated hepatocyte fibronectin (FN1), which trafficked to bone marrow and activated osteoclasts via integrin αv. Serum FN1 levels were elevated in cirrhosis patients, correlated with reduced vertebral bone density, and associated with osteoclast activity in mice. Genetic ablation or hepatocyte-specific knockdown of FN1 attenuated bone resorption and improved trabecular architecture. Pharmacologic inhibition of the FN1-integrin αv pathway with CWHM12 reduced osteoclast activity, rescued bone mass, and concurrently ameliorated hepatic fibrosis.

Conclusion: These findings establish hepatic VDR as a central modulator of cirrhosis-associated osteoporosis through FN1-mediated integrin signaling. Targeting the VDR-FN1-integrin αv axis offers a dual therapeutic opportunity for managing both hepatic fibrosis and osteoporosis in cirrhosis.