Fanca deficiency is associated with alterations in osteoclastogenesis that are rescued by TNFα

• Published in: Cell & bioscience Vol. 13; no. 1; p. 115
• Main Authors: Oppezzo, Alessia, Monney, Lovely, Kilian, Henri, Slimani, Lofti, Maczkowiak-Chartois, Frédérique, Rosselli, Filippo
• Format: Journal Article
• Language: English
• Published: England BioMed Central 24-06-2023; BMC
• Subjects: Biosynthesis; Bone marrow; Bone turnover; Cell self-renewal; Cell signaling; Cyclin-dependent kinases; DNA damage; DNA repair; Drug dosages; Fanconi anemia; Fanconi syndrome; Genes; Hematopoietic stem cells; Hemopoiesis; Homeostasis; Inflammation; Kinases; Life Sciences; Mutation; NF-κB protein; Osteoblast; Osteoblasts; Osteoclast; Osteoclastogenesis; Osteoclasts; Osteoporosis; p53; p53 Protein; Proteins; TNFα; Transcription factors; Tumor necrosis factor-α; Osteoblast; TNFα; Osteoclast; Fanconi anemia; Cell signaling; p53
• ISSN: 2045-3701; 2045-3701
• DOI: 10.1186/s13578-023-01067-7

Hematopoietic stem cells (HSCs) reside in the bone marrow (BM) niche, which includes bone-forming and bone-resorbing cells, i.e., osteoblasts (OBs) and osteoclasts (OCs). OBs originate from mesenchymal progenitors, while OCs are derived from HSCs. Self-renewal, proliferation and differentiation of HSCs are under the control of regulatory signals generated by OBs and OCs within the BM niche. Consequently, OBs and OCs control both bone physiology and hematopoiesis. Since the human developmental and bone marrow failure genetic syndrome fanconi anemia (FA) presents with skeletal abnormalities, osteoporosis and HSC impairment, we wanted to test the hypothesis that the main pathological abnormalities of FA could be related to a defect in OC physiology and/or in bone homeostasis.
We revealed here that the intrinsic differentiation of OCs from a Fanca
mouse is impaired in vitro due to overactivation of the p53-p21 axis and defects in NF-kB signaling. The OC differentiation abnormalities observed in vitro were rescued by treating Fanca
cells with the p53 inhibitor pifithrin-α, by treatment with the proinflammatory cytokine TNFα or by coculturing them with Fanca-proficient or Fanca-deficient osteoblastic cells.
Overall, our results highlight an unappreciated role of Fanca in OC differentiation that is potentially circumvented in vivo by the presence of OBs and TNFα in the BM niche.