Excess glucocorticoids inhibit murine bone turnover via modulating the immunometabolism of the skeletal microenvironment
Xu Li, Tongzhou Liang, Bingyang Dai, Liang Chang, Yuan Zhang, Shiwen Hu, Jiaxin Guo, Shunxiang Xu, Lizhen Zheng, Hao Yao, Hong Lian, Yu Nie, Ye Li, Xuan He, Zhi Yao, Wenxue Tong, Xinluan Wang, Dick Ho Kiu Chow, Jiankun Xu, Ling Qin
Xu Li, Tongzhou Liang, Bingyang Dai, Liang Chang, Yuan Zhang, Shiwen Hu, Jiaxin Guo, Shunxiang Xu, Lizhen Zheng, Hao Yao, Hong Lian, Yu Nie, Ye Li, Xuan He, Zhi Yao, Wenxue Tong, Xinluan Wang, Dick Ho Kiu Chow, Jiankun Xu, Ling Qin
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Research Article Bone biology

Excess glucocorticoids inhibit murine bone turnover via modulating the immunometabolism of the skeletal microenvironment

Abstract

Elevated bone resorption and diminished bone formation have been recognized as the primary features of glucocorticoid-associated skeletal disorders. However, the direct effects of excess glucocorticoids on bone turnover remain unclear. Here, we explored the outcomes of exogenous glucocorticoid treatment on bone loss and delayed fracture healing in mice and found that reduced bone turnover was a dominant feature, resulting in a net loss of bone mass. The primary effect of glucocorticoids on osteogenic differentiation was not inhibitory; instead, they cooperated with macrophages to facilitate osteogenesis. Impaired local nutrient status — notably, obstructed fatty acid transportation — was a key factor contributing to glucocorticoid-induced impairment of bone turnover in vivo. Furthermore, fatty acid oxidation in macrophages fueled the ability of glucocorticoid-liganded receptors to enter the nucleus and then promoted the expression of BMP2, a key cytokine that facilitates osteogenesis. Metabolic reprogramming by localized fatty acid delivery partly rescued glucocorticoid-induced pathology by restoring a healthier immune-metabolic milieu. These data provide insights into the multifactorial metabolic mechanisms by which glucocorticoids generate skeletal disorders, thus suggesting possible therapeutic avenues.

Authors

Xu Li, Tongzhou Liang, Bingyang Dai, Liang Chang, Yuan Zhang, Shiwen Hu, Jiaxin Guo, Shunxiang Xu, Lizhen Zheng, Hao Yao, Hong Lian, Yu Nie, Ye Li, Xuan He, Zhi Yao, Wenxue Tong, Xinluan Wang, Dick Ho Kiu Chow, Jiankun Xu, Ling Qin

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Figure 10

The fabricated fatty acid–containing nanoparticles reprogram macrophage metabolism.

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The fabricated fatty acid–containing nanoparticles reprogram macrophage ...
(A and B) Representative microscopy of FA-LNP (red) uptake by macrophages (A) or BSMPs (B) at specific time points (scale bars: 100 μm). (C and D) Flow cytometry quantification of FA-LNP uptake by macrophages (C) or BSMPs (D) (n = 3). (E) Intracellular ATP in macrophages and BSMPs, exposed to normal-serum or low-serum condition, with or without the addition of FA-LNPs (n = 5–6). (F) Under low-serum condition (1% FBS), transcription levels of BMP2 in macrophages exposed to Dex and/or FA-LNPs (n = 3). (G) Under low-serum condition (1% FBS), BMP2 production from macrophages exposed to Dex and/or FA-LNPs (n = 3) with transfection of vehicle or Cpt1a shRNA. (H and I) Representative microscopy of macrophages (after exposure to different serum conditions, Dex, and/or FA-LNPs) stained for GR (H) and quantification of nuclear localization (I) (n = 100). Scale bar: 50 μm. (J) Occupancy of GR at the BMP2 promoter of macrophages (after exposure to low-serum conditions, H-Dex, and/or FA-LNPs) (n = 3). (K) Osteogenic differentiation of BSMPs (with or without addition of macrophages) exposed to normal-serum or low-serum condition, with or without the addition of FA-LNPs, assessed by ALP or ARS staining. Dex, 10–6 M dexamethasone. *P < 0.05, **P < 0.01, ***P < 0.001 by 2-way ANOVA (E–G and I) with Bonferroni’s post hoc test or 2-tailed Student’s t test (J).