Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cell Metab. 2023 Apr 4;35(4):667-684.e6. doi: 10.1016/j.cmet.2023.03.005.
The chronic use of glucocorticoids decreases bone mass and quality and increases bone-marrow adiposity, but the underlying mechanisms remain unclear. Here, we show that bone-marrow adipocyte (BMAd) lineage cells in adult mice undergo rapid cellular senescence upon glucocorticoid treatment. The senescent BMAds acquire a senescence-associated secretory phenotype, which spreads senescence in bone and bone marrow. Mechanistically, glucocorticoids increase the synthesis of oxylipins, such as 15d-PGJ2, for peroxisome proliferator-activated receptor gamma (PPARγ) activation. PPARγ stimulates the expression of key senescence genes and also promotes oxylipin synthesis in BMAds, forming a positive feedback loop. Transplanting senescent BMAds into the bone marrow of healthy mice is sufficient to induce the secondary spread of senescent cells and bone-loss phenotypes, whereas transplanting BMAds harboring a p16INK4a deletion did not show such effects. Thus, glucocorticoid treatment induces a lipid metabolic circuit that robustly triggers the senescence of BMAd lineage cells that, in turn, act as the mediators of glucocorticoid-induced bone deterioration.
长期使用糖皮质激素会减少骨量和骨质量，增加骨髓脂肪含量，但潜在机制尚不清楚。在这里，我们表明成年小鼠骨髓脂肪细胞（BMAd）谱系细胞在糖皮质激素治疗下会迅速发生细胞衰老。衰老的 BMAd 获得衰老相关的分泌表型，从而在骨骼和骨髓中传播衰老。在机制上，糖皮质激素增加了过氧化物酶体增殖物激活受体 γ（PPARγ）激活所需的氧化脂类，如 15d-PGJ2 的合成。PPARγ 刺激关键衰老基因的表达，并促进 BMAd 中氧化脂类的合成，形成正反馈回路。将衰老的 BMAd 移植到健康小鼠的骨髓中足以诱导衰老细胞和骨丢失表型的二次传播，而移植携带 p16INK4a 缺失的 BMAd 则没有显示出这种效果。因此，糖皮质激素治疗诱导了一个脂质代谢回路，强烈触发 BMAd 谱系细胞的衰老，而这些细胞反过来又充当糖皮质激素诱导的骨恶化的介质。
