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
Figure 4
Blockade of Th17 cell influx into BM by treatment with anti-CCL20 Ab prevents expansion of Th17 cells and bone loss induced by ovx.
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)