Sickle cell disease (SCD) is a worldwide distributed hereditary red cell disorder, characterized by severe organ complication. Sickle bone disease (SBD) affects the large part of SCD patients and its pathogenesis has been only partially investigated. Here, we studied bone homeostasis in 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 up-regulation of Il6 as pro-resorptive cytokine. This was associated with further suppression of osteogenic lineage (Runx2, Sparc). In order to interfer with the development of SBD, zoledronic-acid, a potent inhibitor of osteoclast activity/osteoclastogenesis and promoter of osteogenic lineage, was used in H/R exposed mice. Zoledronic-acid 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 to either normoxic or single H/R episode SCD mice. Zoledronic-acid 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 pro-resorptive cytokine such as IL6. Zoledronic acid might act on both osteoclast and osteoblast compartment as multimodal therapy to prevent SBD.

Hypoxia-reperfusion affects osteogenic lineage and promotes sickle cell bone disease

DALLE CARBONARE, Luca Giuseppe;MATTE', Alessandro;VALENTI, Maria Teresa
;
SICILIANO, Angela;MORI, Antonio;SCHWEIGER, Vittorio;PERBELLINI, Luigi;DE FRANCESCHI, Lucia
2015

Abstract

Sickle cell disease (SCD) is a worldwide distributed hereditary red cell disorder, characterized by severe organ complication. Sickle bone disease (SBD) affects the large part of SCD patients and its pathogenesis has been only partially investigated. Here, we studied bone homeostasis in 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 up-regulation of Il6 as pro-resorptive cytokine. This was associated with further suppression of osteogenic lineage (Runx2, Sparc). In order to interfer with the development of SBD, zoledronic-acid, a potent inhibitor of osteoclast activity/osteoclastogenesis and promoter of osteogenic lineage, was used in H/R exposed mice. Zoledronic-acid 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 to either normoxic or single H/R episode SCD mice. Zoledronic-acid 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 pro-resorptive cytokine such as IL6. Zoledronic acid might act on both osteoclast and osteoblast compartment as multimodal therapy to prevent SBD.
Sickle cell disease (SCD), Sickle bone disease (SBD), bone homeostasis, Zoledronic acid
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/927352
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