The RANKL-RANK Axis: A Bone to Thymus Round Trip.

Cristina Sobacchi,Anna Villa,Ciro Menale

doi:10.3389/fimmu.2019.00629

Abstract

The identification of Receptor activator of nuclear factor kappa B ligand (RANKL) and its cognate receptor Receptor activator of nuclear factor kappa B (RANK) during a search for novel tumor necrosis factor receptor (TNFR) superfamily members has dramatically changed the scenario of bone biology by providing the functional and biochemical proof that RANKL signaling via RANK is the master factor for osteoclastogenesis. In parallel, two independent studies reported the identification of mouse RANKL on activated T cells and of a ligand for osteoprotegerin on a murine bone marrow-derived stromal cell line. After these seminal findings, accumulating data indicated RANKL and RANK not only as essential players for the development and activation of osteoclasts, but also for the correct differentiation of medullary thymic epithelial cells (mTECs) that act as mediators of the central tolerance process by which self-reactive T cells are eliminated while regulatory T cells are generated. In light of the RANKL-RANK multi-task function, an antibody targeting this pathway, denosumab, is now commonly used in the therapy of bone loss diseases including chronic inflammatory bone disorders and osteolytic bone metastases; furthermore, preclinical data support the therapeutic application of denosumab in the framework of a broader spectrum of tumors. Here, we discuss advances in cellular and molecular mechanisms elicited by RANKL-RANK pathway in the bone and thymus, and the extent to which its inhibition or augmentation can be translated in the clinical arena.

Highlights

Receptor activator of nuclear factor kappa B (RANK) and its ligand (RANKL), encoded, respectively, by the Tumor necrosis factor receptor superfamily member 11A (Tnfrsf11a) and the Tumor necrosis factor ligand superfamily member 11 (Tnfsf11) genes, constitute a receptor-ligand pair initiating a signaling pathway of paramount relevance in many pathophysiological contexts [1]
Mature medullary thymic epithelial cells mediate central tolerance process by expressing the transcriptional coactivator AutoImmune Regulator (AIRE), which drives the expression of self-antigens, including tissue restricted antigens (TRAs) leading to the clonal deletion of autoreactive T cells, while inducing the generation of regulatory T cells [67, 68], and the intrathymic positioning of X-C Motif Chemokine Ligand 1 (XCL1)+ dendritic cells [69]
Of note, during embryonic life at the initial stages of thymus development, invariant Vγ5+ dendritic epidermal T cells (DETCs) and Vγ5+ γδ T cells T cells contribute to central tolerance establishment by promoting CD80−Aire− medullary Thymic Epithelial Cell (mTEC) to become CD80+Aire+ mTECs [84,85,86] supporting a critical role for RANK signaling in the interaction between fetal γδ T cell progenitors and mTECs [87, 88]

Summary

Introduction

Receptor activator of nuclear factor kappa B (RANK) and its ligand (RANKL), encoded, respectively, by the Tumor necrosis factor receptor superfamily member 11A (Tnfrsf11a) and the Tumor necrosis factor ligand superfamily member 11 (Tnfsf11) genes, constitute a receptor-ligand pair initiating a signaling pathway of paramount relevance in many pathophysiological contexts [1]. Mature medullary thymic epithelial cells (mTECs) mediate central tolerance process by expressing the transcriptional coactivator AutoImmune Regulator (AIRE), which drives the expression of self-antigens, including tissue restricted antigens (TRAs) leading to the clonal deletion of autoreactive T cells, while inducing the generation of regulatory T cells [67, 68], and the intrathymic positioning of X-C Motif Chemokine Ligand 1 (XCL1)+ dendritic cells [69].

Results

Conclusion