The Role of IL-17 and TH17 Cells in the Bone Catabolic Activity of PTH

Abstract

Osteoimmunology is field of research dedicated to the study of the interactions between the immune system and bone. Among the cells of the immune system that regulate the skeleton in health and disease are T lymphocytes, T cells secrete inflammatory/osteoclastogenic cytokines such as RANKL, TNF, and IL-17, as well as factors that stimulate bone formation, including Wnt ligands. In addition, T cells regulate the differentiation and life span of stromal cells via CD40L and other costimulatory molecules expressed on their surface. Consensus exists that parathyroid hormone (PTH) induces bone loss by increasing the production of RANKL by osteocytes and osteoblast. However, new evidence suggests that PTH expands Th17 cells and increases IL-17 levels in mice and humans. Studies in the mouse of further shown that Th17 cell produced IL-17 acts as an "upstream cytokine" that increases the sensitivity of osteoblasts and osteocytes to PTH. As a result, PTH stimulates osteocytic and osteoblastic release of RANKL. Therefore, PTH cause bone loss only in the presence of IL-17 signaling. This article reviews the evidence that the effects of PTH are mediated not only by osteoblasts and osteocytes, but also T cells and IL-17.

Keywords: IL-17; PTH; T cells; bone; osteoblasts; osteocytes.

Figure 1

Schematic representation of the mechanism of action of cPTH in bone. PTH binds to the PTH receptor PPR expressed in conventional CD4⁺ and Cd8⁺ T cells and induces the secretion of TNF. This cytokines induces the differentiation of naive CD4⁺ cells into Th17 cells via TNFR1 signaling. Th17 cells release additional TNF, which further stimulates Th17 differentiation. More importantly, Th17 cells secrete IL-17, which targets osteocytes and osteoblasts, thus increasing their sensitivity to TNF. In the presence of IL-17, PPR activation in osteocytes and osteoblasts stimulates these cells to release RANKL, which stimulates bone resorption and induces bone loss. Silencing of IL-17 or IL-17RA signaling blocks the capacity of cPTH to stimulate the production of RANKL by osteocytes and osteoblasts. Reproduced with permission from Ref. (24).

Figure 2

Levels (Median ± interquartile range) of IL-17A (Panel A) and RORC mRNAs (Panel B) in healthy controls (n = 57) and subjects with PHPT before (n = 20) and after parathyroidectomy (n = 20). Data were analyzed by Mann–Whitney (healthy controls vs. PHPT before surgery and healthy controls vs. PHPT after surgery) and Wilcoxon matched pairs signed rank tests (PHPT vs. PHPT after surgery) as the data were not normally distributed according to the Shapiro–Wilk normality test. Reproduced with permission from Ref. (24).