Bone Abstracts

Fanconi anemia (FA) is a rare genetic disease associated with a progressive decline in hematopoietic stem cells leading to bone marrow failure. FA is also characterized by various developmental defects including short stature and skeletal malformations of the upper and lower limbs. Indeed, more than half of children affected with FA have radial-ray abnormalities with a tendency to early osteoporosis and osteopenia. However, the underlying mechanisms leading to bone defects in FA remains elusive.

Objective: We aimed to determine the mechanism leading to altered bone development and metabolism in FA.

Methods: Bone structure, mass and mineral content were evaluated using μCT-scan analyses of tibias from FancC^−/− and wild-type mice. Bone’s resorption activity was determined with tartrate-resistant acid phosphatase staining. To evaluate skeletal maturation, alizarin red and Alcian blue double staining were performed on mouse embryos (E15.5 to 19.5 dpc). To assess mesenchymal stem cell differentiation ability, in-vitro cultures and qPCR analysis of bone marrow stromal cells were performed.

Results: Our results show that FancC^−/− mice present a 15% decrease in bone mineral content, reduced cortical thickness and diameter combined with a 15% reduction of the bone marrow area. FancC^−/− mice also present elevated tartrate-resistant acid phosphatase staining as compared to wild-type littermates. In addition, FancC^−/− embryos show abnormal skeletal development indicated by decreased bone length and mineralization. Using in vitro studies, we found that FancC^−/− mesenchymal stem cells (MSC) have reduced osteoblastic differentiation capabilities and engraftment potential in favor of adipogenesis. Accordingly, FA-defective MSC present altered gene expression profiles of differentiation markers.

Conclusion: Together, our results suggest that defective bone metabolism in FA occurs in utero and results from altered MSCs function. These results provide, for the first time, valuable insights into the mechanism involved in FA developmental defects.

Disclosure The authors declared no competing interests.