Physiological and genomic consequences of intermittent hypoxia: Selected contribution: Osteocytes upregulate HIF-1α in response to acute disuse and oxygen deprivation

Gross, Ted S., Nagako Akeno, Thomas L. Clemens, Svetlana Komarova, Sundar Srinivasan, David A. Weimer, and Sergey Mayorov. Selected Contribution: Osteocytes upregulate HIF-1a in response to acute disuse and oxygen deprivation. J Appl Physiol 90: 2514–2519, 2001.—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 hypoxiadependent transcription factor HIF-1a. We found that acute disuse (1–5 days) resulted in a significant increase in the percentage of osteocytes staining positive for HIF-1a vs. normal bone (30.9 6 6.1 vs. 14.1 6 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 2.1to 3.7-fold upregulation of HIF-1a protein expression in MLO-Y4 osteocyte-like cells compared with cells cultured in parallel under normal oxygen conditions. Given known HIF-1a targets genes, we suggest that osteocyte hypoxia and subsequent upregulation of hypoxia-dependent pathways may serve to initiate and mediate disuseinduced bone resorption.