PTH induces bone loss via microbial-dependent expansion of intestinal TNF+ T cells and Th17 cells

Bone loss is a frequent but not universal complication of hyperparathyroidism. Using antibiotic-treated or germ-free mice, we show that parathyroid hormone (PTH) only caused bone loss in mice whose microbiota was enriched by the Th17 cell-inducing taxa segmented filamentous bacteria (SFB). SFB+ microbiota enabled PTH to expand intestinal TNF+ T and Th17 cells and increase their S1P-receptor-1 mediated egress from the intestine and recruitment to the bone marrow (BM) that causes bone loss. CXCR3-mediated TNF+ T cell homing to the BM upregulated the Th17 chemoattractant CCL20, which recruited Th17 cells to the BM. This study reveals mechanisms for microbiota-mediated gut–bone crosstalk in mice models of hyperparathyroidism that may help predict its clinical course. Targeting the gut microbiota or T cell migration may represent therapeutic strategies for hyperparathyroidism.

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Bone marrow cells was collected from pelvic bones by centrifugation for 2 min at 12000 rpm. Red cells were removed with red blood cell lysis buffer (Biolegend) before antibody staining. For Peyer's patches (PP) cell isolation, the small intestine was removed and flushed of fecal content. PPs were excised and collected in 1 ml cooled RPMI1640. PPs were dissociated using the plunger of a 2.5 ml syringe and gently forced through a 70 µm cell strainer placed over a 50 ml tube. A single cell suspension was used for analysis by flow cytometry.

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