Selected Contribution: Osteocytes upregulate HIF-1alpha in response to acute disuse and oxygen deprivation.

Loss of mechanical loading, or disuse, rapidly precipitates locally mediated bone resorption. However, the pathway by which this process is initiated and mediated is poorly understood. In this study, we used a complementary in vivo and in vitro approach to determine whether disuse-induced osteocyte hypoxia resulted in upregulation of the hypoxia-dependent transcription factor HIF-1alpha. We found that acute disuse (1-5 days) resulted in a significant increase in the percentage of osteocytes staining positive for HIF-1alpha vs. normal bone (30.9 +/- 6.1 vs. 14.1 +/- 3.8%) and that this response was uniform around the cortex. In addition, we found that acute oxygen deprivation (4-12 h of 2% O2) resulted in a 2.1- to 3.7-fold upregulation of HIF-1alpha protein expression in MLO-Y4 osteocyte-like cells compared with cells cultured in parallel under normal oxygen conditions. Given known HIF-1alpha targets genes, we suggest that osteocyte hypoxia and subsequent upregulation of hypoxia-dependent pathways may serve to initiate and mediate disuse-induced bone resorption.