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 impairm...
Source: Blood - Category: Hematology Authors: Tags: Sickle Cell Disease, Red Cells, Iron, and Erythropoiesis Source Type: research