Impacts of Hypoxia on Osteoclast Formation and Activity: Systematic Review

Abstract

Hypoxia is evident in several bone diseases which are characterized by excessive bone resorption by osteoclasts, the bone-resorbing cells. The effects of hypoxia on osteoclast formation and activities are widely studied but remain inconclusive. This systematic review discusses the studies reporting the effect of hypoxia on osteoclast differentiation and activity. A literature search for relevant studies was conducted through SCOPUS and PUBMED MEDLINE search engines. The inclusion criteria were original research articles presenting data demonstrating the effect of hypoxia or low oxygen on osteoclast formation and activity. A total of 286 studies were identified from the search, whereby 20 studies were included in this review, consisting of four in vivo studies and 16 in vitro studies. In total, 12 out of 14 studies reporting the effect of hypoxia on osteoclast activity indicated higher bone resorption under hypoxic conditions, 14 studies reported that hypoxia resulted in more osteoclasts, one study found that the number remained unchanged, and five studies indicated that the number decreased. In summary, examination of the relevant literature suggests differences in findings between studies, hence the impact of hypoxia on osteoclasts remains debatable, even though there is more evidence to suggest it promotes osteoclast differentiation and activity.

Osteometabolism: Metabolic Alterations in Bone Pathologies

“…HIF proteins such as HIF-1α or HIF-2α, which are also the transcription factors that mediate hypoxia-related pathways, are often highly expressed in hypoxic circumstances. HIF-1α is constitutively hydroxylated in the presence of oxygen and is then targeted for proteasomal destruction [ 57 ]. Under hypoxic conditions, however, this does not happen, allowing HIF- 1α to stay stable in the cell and be able to dimerize with HIF- 1β before binding to the hypoxia-response element and starting the transcription of HIF target genes [ 57 ].…”

“…HIF-1α is constitutively hydroxylated in the presence of oxygen and is then targeted for proteasomal destruction [ 57 ]. Under hypoxic conditions, however, this does not happen, allowing HIF- 1α to stay stable in the cell and be able to dimerize with HIF- 1β before binding to the hypoxia-response element and starting the transcription of HIF target genes [ 57 ]. Studies suggest contradictory results of hypoxic conditions on osteoblastogenesis; however, the duration and concentration of hypoxic conditions need further investigation.…”

Strontium Peroxide-Loaded Composite Scaffolds Capable of Generating Oxygen and Modulating Behaviors of Osteoblasts and Osteoclasts

“…It was reported that under hypoxic conditions (e.g., 1% oxygen concentration), the proliferation and differentiation potential of osteoblasts is remarkably inhibited [ 61 , 62 ]. Furthermore, the hypoxic niche contributes significantly to the activation of osteoclasts for bone resorption [ 63 , 64 ]. Therefore, further investigations of the synergistic effects of oxygen and Sr 2+ released by the developed scaffold system are warranted in terms of promoting osteoblast proliferation/differentiation and suppressing osteoclast formation to further highlight the potential benefits of SrO 2 + MnO 2 @PLGA/gelatin.…”

Changes in Metabolism and Mitochondrial Bioenergetics during Polyethylene-Induced Osteoclastogenesis

“…In this study, we focus on the changes in mitochondrial bioenergetic parameters, glycolysis efficiency, and profile of substrates fueling mitochondrial respiration during PE-induced osteoclast differentiation, and how these could be affected by TRF treatment. From our published systematic review [ 53 ]—even though a majority of the literature has reported an increase in osteoclastogenesis following hypoxia—some studies have indicated otherwise. This may suggest that both aerobic and anaerobic respiration are important during osteoclastogenesis; hence, both OXPHOS and glycolysis, as well as the oxidation of metabolic substrates, should be examined in osteoclasts.…”