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

Area of Science:

• Immunology
• Microbiology
• Endocrinology
• Bone Biology

Background:

• Bone loss is a common complication of hyperparathyroidism, but the underlying mechanisms are not fully understood.
• The role of the gut microbiota in mediating systemic effects of parathyroid hormone (PTH) on bone metabolism is an emerging area of research.

Purpose of the Study:

• To investigate the role of gut microbiota in mediating PTH-induced bone loss.
• To elucidate the cellular and molecular mechanisms of microbiota-gut-bone crosstalk in hyperparathyroidism.

Main Methods:

• Utilized antibiotic-treated and germ-free mouse models to assess the impact of microbiota depletion.
• Administered parathyroid hormone (PTH) and analyzed changes in intestinal and bone marrow immune cell populations, including T helper 17 (Th17) cells.
• Investigated the involvement of specific molecular pathways, such as S1P-receptor-1 and CXCR3, in T cell migration and bone loss.

Main Results:

• PTH induced bone loss exclusively in mice with segmented filamentous bacteria (SFB)-enriched microbiota.
• SFB⁺ microbiota promoted the expansion of intestinal TNF⁺ T and Th17 cells.
• PTH increased S1P-receptor-1 mediated egress of these cells from the intestine and their recruitment to the bone marrow (BM).
• CXCR3-mediated T cell homing to the BM upregulated CCL20, attracting Th17 cells and leading to bone loss.

Conclusions:

• Gut microbiota, particularly SFB, is critical for PTH-induced bone loss.
• Microbiota-mediated gut-bone crosstalk involves T cell expansion, migration to the bone marrow, and subsequent bone resorption.
• Targeting the gut microbiota or T cell migration pathways presents potential therapeutic strategies for hyperparathyroidism-associated bone loss.