Integrative Omics Reveals Glutamine Catabolism‐Driven Apoptotic Suppression in Monocytes upon Mechanical Unloading

Abstract Osteoclasts derived bone marrow monocytes have been documented to modulate bone quality by directly sensing mechanical forces. However, the mechanisms by which osteoclasts perceive and respond to mechanical disturbances remain unclear. Through integrating multi‐omics data of bone tissues from hindlimb unloading (HLU) and control mice, it is revealed that glutamine (Gln) catabolism‐induced suppression of apoptosis is critical for monocytes sensing and responding to mechanical unloading. Gln uptake is essential for the survival of monocytes under mechanical unloading. Deprivation of Gln or blockade of Gln transporter solute carrier family 1 member 5 (SLC1A5) inhibits bone resorption by enhancing apoptosis of monocytes. Unloading exposure‐induced cell survival is mediated by X‐linked inhibitor of apoptosis protein (XIAP)/direct IAP binding protein with low pI (Diablo) axis. Upon mechanical unloading XIAP is upregulated, then interacts with Diablo in mitochondrial and promotes the K63‐linkage ubiquitylation of Diablo at the K212 site. This sequesters Diablo within the mitochondrial and inhibits its release into the cytosol, ultimately inhibiting cell apoptosis of osteoclasts and the precursors. Clinically, the serum Gln levels are positively correlated with cross linked C‐telopeptide of type I collagen (CTX) levels, indicating that serum Gln levels might serve as a potential biomarker for predicting the risk of osteoporosis. Gln‐deficient diet, as well as SLC1A5 inhibitor L‐γ‐Glutamyl‐p‐nitroanilide (GPNA), effectively preserves bone mass in HLU mice, implicating attractive approaches for combating bone loss induced by weightlessness or disuse.