Excess glucocorticoids inhibit murine bone turnover via modulating the immunometabolism of the skeletal microenvironment
Xu Li, … , Jiankun Xu, Ling Qin
Xu Li, … , Jiankun Xu, Ling Qin
Published March 21, 2024
Citation Information: J Clin Invest. 2024;134(10):e166795. https://doi.org/10.1172/JCI166795.
View: Text | PDF
Research Article Bone biology Article has an altmetric score of 1

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

×

Figure 9

Fatty acids fuel macrophages to promote osteogenesis.

Options: View larger image (or click on image) Download as PowerPoint
Fatty acids fuel macrophages to promote osteogenesis. (A) Mitochondrial ...
(A) Mitochondrial content in macrophages under different culture conditions, as measured by MitoTracker Green (Thermo Fisher Scientific) (n = 3). (B) BMP2 production from macrophages exposed to palmitic acid and/or oleic acid (n = 3). (C–E) Representative images of macrophages stained for GR and quantification of nuclear localization (n = 100; scale bars: 50 μm). (C) Cells were transfected with vehicle or Cpt1a shRNA (n = 100). (D) Cells were treated with SSO (n = 100). (E) Cells were treated with palmitic acid and/or oleic acid (n = 100). (F–H) Occupancy of GR at the BMP2 promoter of macrophages exposed to different culture conditions. (F) Cells were transfected with Cpt1a shRNA (n = 4). (G) Cells were treated with SSO (n = 3). (H) Cells were treated with palmitic acid and/or oleic acid (n = 3). (I) ALP (at day 5) and ARS (at day 10) staining of BSMPs cultured with supernatants from low serum– and H-Dex–pretreated macrophages with the addition of palmitic acid, SSO, and/or BMP2 siRNA. Low serum, 1% FBS culture condition; Dex, 10–6 M dexamethasone. Data are mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001 by 2-way ANOVA (A, B, and E), 1-way ANOVA (C, D, F, and G) with Bonferroni’s post hoc test, or 2-tailed Student’s t test (H).