| Summary: | Bone formation is driven by many signaling molecules including bone morphogenetic protein 9 (BMP-9) and hypoxia-inducible factor 1-alpha (HIF-1α). We demonstrated that cell therapy using mesenchymal stem cells (MSCs) overexpressing BMP-9 (MSCs<sup>+BMP-9</sup>) enhances bone formation in calvarial defects. Here, the effect of hypoxia on BMP components and targets of MSCs<sup>+BMP-9</sup> and of these hypoxia-primed cells on osteoblast differentiation and bone repair was evaluated. Hypoxia was induced with cobalt chloride (CoCl<sub>2</sub>) in MSCs<sup>+BMP-9</sup>, and the expression of BMP components and targets was evaluated. The paracrine effects of hypoxia-primed MSCs<sup>+BMP-9</sup> on cell viability and migration and osteoblast differentiation were evaluated using conditioned medium. The bone formation induced by hypoxia-primed MSCs<sup>+BMP-9</sup> directly injected into rat calvarial defects was also evaluated. The results demonstrated that hypoxia regulated BMP components and targets without affecting BMP-9 amount and that the conditioned medium generated under hypoxia favored cell migration and osteoblast differentiation. Hypoxia-primed MSCs<sup>+BMP-9</sup> did not increase bone repair compared with control MSCs<sup>+BMP-9</sup>. Thus, despite the lack of effect of hypoxia on bone formation, the enhancement of cell migration and osteoblast differentiation opens windows for further investigations on approaches to modulate the BMP-9-HIF-1α circuit in the context of cell-based therapies to induce bone regeneration.
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