Bone phenotyping of murine hemochromatosis models with deficiencies of Hjv, Alk2, or Alk3: The influence of sex and the bone compartment

• Published in: The FASEB journal 2024-11, Vol.38 (22), p.e70179-n/a
• Main Authors: Dogan, Deniz Y., Hornung, Isabelle, Pettinato, Mariateresa, Pagani, Alessia, Baschant, Ulrike, Seebohm, Guiscard, Hofbauer, Lorenz C., Silvestri, Laura, Rauner, Martina, Steinbicker, Andrea U.
• Format: Article
• Language: English
• Subjects: Activin Receptors, Type I - deficiency; Activin Receptors, Type I - genetics; Activin Receptors, Type I - metabolism; Activin Receptors, Type II - genetics; Activin Receptors, Type II - metabolism; Animals; Bone and Bones - metabolism; Bone and Bones - pathology; Disease Models, Animal; Female; GPI-Linked Proteins; Hemochromatosis - genetics; Hemochromatosis - metabolism; Hemochromatosis - pathology; Hemochromatosis Protein - genetics; Hemochromatosis Protein - metabolism; Iron Overload - genetics; Iron Overload - metabolism; Iron Overload - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Sex Factors
• ISSN: 0892-6638; 1530-6860; 1530-6860
• DOI: 10.1096/fj.202401015R

Osteopenia is frequently observed in patients with iron overload, especially in those with HFE‐dependent hereditary hemochromatosis (HH). Interestingly, not all mouse models of HH show bone loss, suggesting that iron overload alone may not suffice to induce bone loss. In this study, the bone phenotypes of Hjv−/− and hepatocyte‐specific Alk2‐ and Alk3‐deficient mice as additional mouse models of HH were investigated to further clarify, how high iron levels lead to bone loss and which signaling mechanisms are operational. Neither male nor female 12‐week‐old Hjv−/− mice had an altered trabecular or cortical bone mass or bone turnover, despite severe iron overload. Male 12‐month‐old Hjv−/− mice even presented with a higher femoral trabecular bone volume compared to wildtype mice. Similarly, female mice with hepatocyte‐specific Alk2 or Alk3 deficiency did not show an altered bone phenotype at 3, 6, and 12 months of age. Male hepatocyte‐specific Alk3‐deficient mice also had a normal trabecular bone mass at all ages analyzed, despite showing increased bone resorption and decreased bone formation parameters. Interestingly, hepatocyte‐specific Alk2‐deficient mice showed reduced femoral trabecular bone at 6 months of age due to suppressed bone formation. Cortical thickness at the femur was reduced in both, 6‐month‐old male hepatocyte‐specific Alk2‐ and Alk3‐deficient mice. Raising hepatocyte‐specific Alk2‐deficient male mice on an iron‐deficient diet rescued the bone phenotype. Taken together, despite iron overload, trabecular bone microarchitecture was not altered in mice deficient of Hjv or Alk3. Only male hepatocyte‐specific Alk2‐deficient mice showed site‐specific lower trabecular and cortical bone mass at the femur, which was dependent on iron. Thus, bone loss does not correlate with the extent of iron overload in these mouse models, but may relate to the amount of iron‐loaded macrophages, as precursors of osteoclasts, in the bone marrow. Iron overload is most severe in Hjv−/− and Alk3fl/fl; Alb‐cre mice, followed by Alk2fl/fl; Alb‐Cre mice and WT mice. Severe hepcidin suppression in Hjv−/− and Alk3fl/fl; Alb‐cre mice leads to lower numbers of iron‐loaded macrophages in the bone marrow. Bone loss is largest in Alk2fl/fl; Alb‐Cre mice, which have the weakest hepcidin suppression and highest number of iron‐loaded cells in the bone marrow.