Osteoimmunology

Abstract

Bone is a crucial element of the skeletal-locomotor system, but also functions as an immunological organ that harbors hematopoietic stem cells (HSCs) and immune progenitor cells. Additionally, the skeletal and immune systems share a number of regulatory molecules, including cytokines and signaling molecules. Osteoimmunology was created as an interdisciplinary field to explore the shared molecules and interactions between the skeletal and immune systems. In particular, the importance of an inseparable link between the two systems has been highlighted by studies on the pathogenesis of rheumatoid arthritis (RA), in which pathogenic helper T cells induce the progressive destruction of multiple joints through aberrant expression of receptor activator of nuclear factor (NF)-κB ligand (RANKL). The conceptual bridge of osteoimmunology provides not only a novel framework for understanding these biological systems but also a molecular basis for the development of therapeutic approaches for diseases of bone and/or the immune system.

Figure 1.

Essential roles of receptor activator of nuclear factor (NF)-κB ligand (RANKL) in the development of the immune organs. RANKL plays an essential role in the differentiation of osteoclasts, the activity of which causes the formation of the bone marrow cavity. In this sense, RANKL is a cytokine critical for the development of the immune organs in vertebrates, including the bone marrow, thymus, lymph node, and gut-associated lymphoid tissue (GALT).

Figure 2.

The nuclear factor of activated T cell (NFAT)c1-centered osteoclastogenic signaling network. Receptor activator of nuclear factor (NF)-κB ligand (RANKL) binds to RANK on osteoclast precursor cells, leading to activating signaling pathways through tumor necrosis factor (TNF) receptor-associated factor (TRAF)6, which includes mitogen-activated protein kinase (MAPK) and NF-κB. Immunoreceptor tyrosine-based activation motif (ITAM) signaling is activated by RANKL mediated by immunoglobulin-like receptors. The NF-κB pathway contributes to the induction and activation of c-Fos and subsequent NFATc1 induction. The NFATc1 activated via Ca²⁺-signaling is essential for the expression of osteoclast-specific genes.

Figure 3.

The mechanism of bone destruction in rheumatoid arthritis (RA). RA bone destruction happens in inflamed synovium at the interface of the immune system and bone. The interleukin (IL)-17 produced by T helper (Th)17 cells up-regulates receptor activator of nuclear factor (NF)-κB ligand (RANKL) expression on synovial fibroblasts and induces inflammatory cytokines such as tumor necrosis factor (TNF)-α, IL-6, and IL-1 from synovial macrophages. RANKL expression on synovial fibroblasts is further up-regulated by these cytokines activating osteoclast precursor cells. The immunoglobulin (Ig)G immune complex directly promotes osteoclast differentiation. RANKL stimulates osteoclastic bone resorption, although the Dickkopf-1 (DKK-1) induced by inflammatory cytokines such as TNF-α suppresses bone formation.