Researchers have established the mechanism behind bone loss caused by chronic liver injury that might lead to the development of therapeutic drugs for hepatic bone disease.
Published in Cell Metabolism, a team of researchers from the Shenzhen Institute of Advanced Technology (SIAT) of the Chinese Academy of Sciences and other collaborators unveil the molecular mechanisms behind bone loss caused by chronic liver injury.
In patients with chronic liver disorder, hepatic osteodystrophy (HOD) is a metabolic bone disease that may result. It is characterised by bone loss, bone density reduction, and destruction of bone structure.
The liver is a central organ in maintaining tissue homeostasis and many hepatic cytokines regulate peripheral organs, including bones. This mutual regulation between the liver and bone is called liver-bone axis, and external stimuli, like alcohol and drugs, can cause liver damage. This would consequently affect bone metabolism and increase the risk of osteoporosis and fragile fractures.
Such fractures caused by HOD pose a challenge to bone reconstruction and severely affect disease prognosis and patients’ quality of life. Hence, it is important to get a better understanding of how HOD works.
From previous studies, it was established that PP2Acα is involved in liver regeneration through a particular cell signalling pathway and that knockout of PP2Acα would increase insulin sensitivity and lessen insulin resistance. However, it is not known if the regulation of PP2Acα in the liver would influence bone metabolism.
In this study, the researchers found that patients with HOD and mouse models of HOD displayed high expression of PP2Acα. “Conditional knockout of PP2Acα in the liver of HOD mice helps the recovery of liver function and alleviates bone loss,” said Professor Chen, who led the research team.
Through serum proteomics analysis, the team screened and observed higher levels of the hepatic factor LCAT expression in PP2Acα conditional knockout mice. LCAT is the liver-bone axis regulator and functions as a cholesterol transferring enzyme, where it transfers cholesterol from peripheral tissues to the liver in a process called reverse cholesterol transport.
“LCAT mediates bone metabolism by maintaining appropriate intracellular cholesterol levels and improves liver function by reversing cholesterol transport from bone tissues to the liver,” said Dr. Lu Ke, first author of the study.
The reverse cholesterol transport process plays a vital role in maintaining liver-bone homeostasis. By having an appropriate intracellular cholesterol level, osteoblast function is promoted and osteoclast differentiation is inhibited.
In HOD patients and HOD mouse models, the researchers found that PP2Acα down-regulated LCAT expression, causing an imbalance of intracellular cholesterol levels. Hence, the researchers’ work has successfully demonstrated that the imbalance of the liver-bone axis advances the development of HOD caused by chronic liver injury. This study presents a potential drug target for the development of pharmaceutical drugs to treat hepatic bone disease.
Source: Lu et al. (2022). Defects in a liver-bone axis contribute to hepatic osteodystrophy disease progression. Cell Metabolism, 34(3), 441-457.