RANK-RANKL-OPG Axis in MASLD: Current Evidence Linking Bone and Liver Diseases and Future Perspectives

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD)-and its worse form, metabolic-associated steatohepatitis (MASH), characterised by inflammation and liver damage-corresponds to the liver's involvement in metabolic syndrome, which constitutes an economic burden for healthcare systems. However, the biomolecular pathways that contribute to steatotic liver disease are not completely clear. Abnormalities of bone metabolism are frequent in people affected by metabolic liver disease, with reduced bone density and an increased risk of fracture. Receptor activator of NF-κB (RANK), receptor activator of NF-κB ligand (RANKL), and osteoprotegerin(OPG) are critical regulators of bone metabolism, performing pleiotropic effects, and may have potential involvement in metabolic disorders like MASLD, resulting in a topic of great interest and intrigue. This narrative review aims to investigate this potential role and its implications in MASLD development and progression and in hepatocellular carcinoma, which represents its worst complication.

Keywords: bone metabolism; chronic liver disease; metabolic dysfunction-associated steatotic liver disease; metabolic-associated steatohepatitis; osteopenia; osteoporosis; vitamin D.

Figure 1

RANK–RANKL–OPG signalling in bone tissue. RANKL–RANK interaction stimulates osteoclast differentiation and activation, promoting bone resorption. On the contrary, OPG improves bone formation preventing RANKL from binding RANK. (Abbreviation: RANKL: receptor activator of NF-κB ligand; RANK: receptor activator of NF-κB; OPG: osteoprotegerin; PTH: parathyroid hormone; TGF-β: transforming growth factor-β; TNFα: tumour necrosis factor-α; IL-1β: interleukin-1β; IL-6: interleukin-6; IL-11: interleukin-11; IL-13: interleukin-13; IL-17: interleukin-17).

Figure 2

Possible involvement of the RANK–RANKL–OPG axis in MASLD development and progression. Current evidence highlights four main mechanisms of hepatic injury mediated by RROa: (1) RANKL–RANK signalling induces insulin resistance in hepatocytes, which is crucial for MASLD development; (2) RANKL promotes macrophage infiltration in the liver, and its levels gradually increase during disease progression; (3) OPG has a pro-fibrotic action stimulating HSCs to produce extracellular matrix; (4) OPG can block TRAIL, preventing it from inducing hepatocyte apoptosis, which is a progression factor for MASLD. (Abbreviation: RANKL: receptor activator of NF-κB ligand; RANK: receptor activator of NF-κB; OPG: osteoprotegerin; TRAIL: TNF-related apoptosis-inducing ligand).

Figure 3

Hypothetical mechanism of action of denosumab in MASLD. RANKL inhibition by denosumab may ameliorate hepatic insulin resistance and prevent macrophage infiltration in the liver. (Abbreviation: RANKL: receptor activator of NF-κB ligand).