Hypoxia-reperfusion affects osteogenic lineage and promotes sickle cell bone disease.
Sickle cell disease (SCD) is a worldwide distributed hereditary red cell disorder, characterized by severe organ complication. Sickle bone disease (SBD) affects a large part of the SCD patient population, and its pathogenesis has been only partially investigated. Here, we studied bone homeostasis in a humanized mouse model for SCD. Under normoxia, SCD mice display bone loss and bone impairment, with increased osteoclast and reduced osteoblast activity. Hypoxia/reperfusion (H/R) stress, mimicking acute vaso-occlusive crises (VOCs), increased bone turnover, osteoclast activity (RankL), and osteoclast recruitment (Rank) with upregulation of IL-6 as proresorptive cytokine. This was associated with further suppression of osteogenic lineage (Runx2, Sparc). To interfere with the development of SBD, zoledronic acid (Zol), a potent inhibitor of osteoclast activity/osteoclastogenesis and promoter of osteogenic lineage, was used in H/R-exposed mice. Zol markedly inhibited osteoclast activity and recruitment, promoting osteogenic lineage. The recurrent H/R stress further worsened bone structure, increased bone turnover, depressed osteoblastogenesis (Runx2, Sparc), and increased both osteoclast activity (RankL, Cathepsin k) and osteoclast recruitment (Rank) in SCD mice compared with either normoxic or single-H/R-episode SCD mice. Zol used before recurrent VOCs prevented bone impairment and promoted osteogenic lineage. Our findings support the view that SBD is related to osteoblast impairment, and increased osteoclast activity resulted from local hypoxia, oxidative stress, and the release of proresorptive cytokine such as IL-6. Zol might act on both the osteoclast and osteoblast compartments as multimodal therapy to prevent SBD.
Department of Medicine, University of Verona and Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy;
Luca
http://orcid.org/0000-0003-3263-6671
L
Dalle Carbonare
Department of Medicine, University of Verona and Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy;
Alessandro
A
Matte'
Department of Medicine, University of Verona and Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy;
Maria Teresa
http://orcid.org/0000-0003-1166-8033
MT
Valenti
Department of Medicine, University of Verona and Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy;
Angela
A
Siciliano
Department of Medicine, University of Verona and Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy;
Antonio
A
Mori
Department of Surgical Science, Anesthesiology, Intensive Care and Pain Therapy Center, University of Verona and Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy;
Vittorio
V
Schweiger
Advanced Consulting Engineering AC&E, Verona, Italy; and.
Gino
G
Zampieri
Department of Public Health and Community Medicine, University of Verona, Verona, Italy.
Luigi
L
Perbellini
Department of Medicine, University of Verona and Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy;
Lucia
L
De Franceschi
D000755:Anemia, Sickle Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001847:Bone Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D056657:Cathepsin K / Q000235:genetics / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology; D004195:Disease Models, Animal; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D015676:Osteonectin / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077211:Zoledronic Acid
D050659:Core Binding Factor Alpha 1 Subunit; D004164:Diphosphonates; D007093:Imidazoles; D015850:Interleukin-6; D015676:Osteonectin; D053245:RANK Ligand; C493716:Runx2 protein, mouse; C578250:SPARC protein, mouse; C505689:Tnfsf11 protein, mouse; D000077211:Zoledronic Acid; D056657:Cathepsin K; C534132:Ctsk protein, mouse