Ovariectomy induces bone loss via microbial-dependent trafficking of intestinal TNF+ T cells and Th17 cells
Mingcan Yu, … , M. Neale Weitzmann, Roberto Pacifici
Mingcan Yu, … , M. Neale Weitzmann, Roberto Pacifici
Published February 15, 2021
Citation Information: J Clin Invest. 2021;131(4):e143137. https://doi.org/10.1172/JCI143137.
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Research Article Bone biology

Ovariectomy induces bone loss via microbial-dependent trafficking of intestinal TNF+ T cells and Th17 cells

Abstract

Estrogen deficiency causes a gut microbiome–dependent expansion of BM Th17 cells and TNF-α–producing T cells. The resulting increased BM levels of IL-17a (IL-17) and TNF stimulate RANKL expression and activity, causing bone loss. However, the origin of BM Th17 cells and TNF+ T cells is unknown. Here, we show that ovariectomy (ovx) expanded intestinal Th17 cells and TNF+ T cells, increased their S1P receptor 1–mediated (S1PR1-mediated) egress from the intestine, and enhanced their subsequent influx into the BM through CXCR3- and CCL20-mediated mechanisms. Demonstrating the functional relevance of T cell trafficking, blockade of Th17 cell and TNF+ T cell egress from the gut or their influx into the BM prevented ovx-induced bone loss. Therefore, intestinal T cells are a proximal target of sex steroid deficiency relevant for bone loss. Blockade of intestinal T cell migration may represent a therapeutic strategy for the treatment of postmenopausal bone loss.

Authors

Mingcan Yu, Subhashis Pal, Cameron W. Paterson, Jau-Yi Li, Abdul Malik Tyagi, Jonathan Adams, Craig M. Coopersmith, M. Neale Weitzmann, Roberto Pacifici

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Figure 5

Blockade of T cell influx into BM by silencing of CXCR3 prevents expansion of TNF+ T cells and Th17 cells and bone loss induced by ovx.

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Blockade of T cell influx into BM by silencing of CXCR3 prevents expansi...
(A) Effects of ovx on the number of BM TNF+ T cells and on the level of Tnf transcripts in WT mice and Cxcr3–/– mice. (B) Effects of ovx on the BM cell transcript levels of Ccl20 in WT mice and Cxcr3–/– mice. (C) Effects of ovx on the number of BM Th17 cells and on the levels of Il17a transcripts in WT mice and Cxcr3–/– mice. (D) Effects of ovx on femoral BV/TV, Tb.Th, Tb.N, and Tb.Sp in WT mice and Cxcr3–/– mice. (E) Effects of ovx on spinal BV/TV, Tb.Th, Tb.N, and Tb.Sp in WT mice and Cxcr3–/– mice. (F) Effects of ovx on serum CTX levels and serum osteocalcin levels in WT mice and Cxcr3–/– mice. (G) Effects of ovx on femoral Ct.Ar and Ct.Th in WT mice and Cxcr3–/– mice. n = 5 mice per group. Data are expressed as mean ± SEM. All data were normally distributed according to the Shapiro-Wilk normality test and analyzed by 2-way ANOVA and post hoc tests applying Bonferroni’s correction for multiple comparisons. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001, compared with the indicated group.