Intermittent Hypoxic Therapy Inhibits Allogenic Bone-Graft Resorption by Inhibition of Osteoclastogenesis in a Mouse Model.

Natasja Leth Bergholt,Tue Wenzel Kragstrup,Casper Bindzus Foldager,Ari Demirel,Ming Ding,Michael Pedersen,Thomas Andersen,Bent Winding Deleuran

doi:10.3390/ijms23010323

Abstract

Systemic Intermittent Hypoxic Therapy (IHT) relies on the adaptive response to hypoxic stress. We investigated allogenic bone-graft resorption in the lumbar spine in 48 mice. The mice were exposed to IHT for 1 week before surgery or 1 week after surgery and compared with controls after 1 and 4 weeks. Complete graft resorption was observed in 33–36% of the animals in the control group, but none in the preoperative IHT group. Increased bone-graft volume was demonstrated by micro-computed tomography in the preoperative IHT group after 1 week (p = 0.03) while a non-significant difference was observed after 4 weeks (p = 0.12). There were no significant differences in the postoperative IHT group. Increased concentration of immune cells was localized in the graft area, and more positive tartrate-resistant acid phosphatase (TRAP) staining was found in controls compared with IHT allogenic bone grafts. Systemic IHT resulted in a significant increase of the major osteoclast inhibitor osteoprotegerin as well as osteogenic and angiogenic regulators Tgfbr3, Fst3l, Wisp1, and Vegfd. Inflammatory cytokines and receptor activator of nuclear factor kappa-B ligand (RANKL) stimulators IL-6, IL-17a, IL-17f, and IL-23r increased after 1 and 4 weeks, and serum RANKL expression remained constant while Ccl3 and Ccl5 decreased. We conclude that the adaptive response to IHT activates numerous pathways leading to inhibition of osteoclastic activity and inhibition of allogenic bone-graft resorption.

Highlights

Hypoxia is a major universal stimulus able to drive proliferation, differentiation, apoptosis and homeostasis of most cell types through local and systemic oxygen sensing [1]
Total bone-graft volume was higher in both Intermittent Hypoxic Therapy (IHT) groups compared with controls (Figure 1a), and this finding was significant for the preoperative IHT group after 4 weeks (p = 0.003) (Figure 1a)
We found that IL-6, IL-17A and IL-17F were increased by IHT at both 1 and 4 weeks compared with controls

Summary

Introduction

Hypoxia is a major universal stimulus able to drive proliferation, differentiation, apoptosis and homeostasis of most cell types through local and systemic oxygen sensing [1]. Local hypoxic cues initiate multiple events responsible for embryogenesis as well as spatial and temporal orchestration of tissue homeostasis [2,3]. Cell survival is dependent on the initial rapid adaptation to hypoxia by hypoxia-inducible factors (HIFs) and mitochondrial reactive oxygen species (ROS) production followed by a prolonged physiological adaptation to hypoxia [4,5]. The adaptive response to short-term hypoxia is being used in endurance athletes to enhance athletic performance and recovery [8]. We define systemic intermittent hypoxic therapy (IHT) as short periods of exposure to lower-than-normal levels of oxygen in the inspired air interrupted by recovery periods

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