Chronic CCl4 intoxication causes liver and bone damage similar to the human pathology of hepatic osteodystrophy: a mouse model to analyse the liver-bone axis

Arch Toxicol. 2014 Apr;88(4):997-1006. doi: 10.1007/s00204-013-1191-5. Epub 2014 Jan 1.


Patients with chronic liver diseases frequently exhibit decreased bone mineral densities (BMD), which is defined as hepatic osteodystrophy (HOD). HOD is a multifactorial disease whose regulatory mechanisms are barely understood. Thus, an early diagnosis and therapy is hardly possible. Therefore, the aim of our study consisted in characterizing a mouse model reflecting the human pathomechanism. Serum samples were collected from patients with chronic liver diseases and 12-week old C57Bl6/N mice after 6-week treatment with carbon tetrachloride (CCl4). Repetitive injections of CCl4 induced liver damage in mice, resembling liver fibrosis in patients, as assessed by serum analysis and histological staining. Although CCl4 did not affect primary osteoblast cultures, μCT analysis revealed significantly decreased BMD, bone volume, trabecular number and thickness in CCl4-treated mice. In both HOD patients and CCl4-treated mice, an altered vitamin D metabolism with decreased CYP27A1, CYP2R1, vitamin D-binding protein GC and increased 7-dehydrocholesterol reductase hepatic gene expression, results in decreased 25-OH vitamin D serum levels. Moreover, both groups exhibit excessively high active transforming growth factor-beta (TGF-β) serum levels, inhibiting osteoblast function in vitro. Summarizing, our mouse model presents possible mediators of HOD, e.g. altered vitamin D metabolism and increased active TGF-β. Liver damage and significant changes in bone structure and mineralization are already visible by μCT analysis after 6 weeks of CCl4 treatment. This fast response and easy transferability makes it an ideal model to investigate specific gene functions in HOD.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / blood
  • Bone Density
  • Bone Diseases, Metabolic / blood
  • Bone Diseases, Metabolic / chemically induced*
  • Bone Diseases, Metabolic / pathology
  • Bone and Bones / diagnostic imaging
  • Bone and Bones / metabolism
  • Bone and Bones / pathology*
  • Carbon Tetrachloride*
  • Case-Control Studies
  • Cells, Cultured
  • Chemical and Drug Induced Liver Injury / blood
  • Chemical and Drug Induced Liver Injury / etiology*
  • Chemical and Drug Induced Liver Injury / pathology
  • Disease Progression
  • Humans
  • Liver / metabolism
  • Liver / pathology*
  • Liver Cirrhosis, Experimental / blood
  • Liver Cirrhosis, Experimental / chemically induced*
  • Liver Cirrhosis, Experimental / pathology
  • Mice, Inbred C57BL
  • Osteoblasts / metabolism
  • Osteoblasts / pathology
  • Species Specificity
  • Time Factors
  • X-Ray Microtomography


  • Biomarkers
  • Carbon Tetrachloride