Updates on Osteoimmunology: What's New on the Cross-Talk Between Bone and Immune System

Abstract

The term osteoimmunology was coined many years ago to describe the research field that deals with the cross-regulation between bone cells and the immune system. As a matter of fact, many factors that are classically considered immune-related, such as InterLeukins (i.e., IL-6, -11, -17, and -23), Tumor Necrosis Factor (TNF)-α, Receptor-Activator of Nuclear factor Kappa B (RANK), and its Ligand (RANKL), Nuclear Factor of Activated T-cell, cytoplasmatic-1 (NFATc1), and others have all been found to be crucial in osteoclast and osteoblast biology. Conversely, bone cells, which we used to think would only regulate each other and take care of remodeling bone, actually regulate immune cells, by creating the so-called "endosteal niche." Both osteoblasts and osteoclasts participate to this niche, either by favoring engraftment, or mobilization of Hematopoietic Stem Cells (HSCs). In this review, we will describe the main milestones at the base of the osteoimmunology and present the key cellular players of the bone-immune system cross-talk, including HSCs, osteoblasts, osteoclasts, bone marrow macrophages, osteomacs, T- and B-lymphocytes, dendritic cells, and neutrophils. We will also briefly describe some pathological conditions in which the bone-immune system cross-talk plays a crucial role, with the final aim to portray the state of the art in the mechanisms regulating the bone-immune system interplay, and some of the latest molecular players in the field. This is important to encourage investigation in this field, to identify new targets in the treatment of bone and immune diseases.

Keywords: RANKL; immune cells; inflammation; osteoblasts; osteoclasts; osteoimmunology; osteoporosis; rheumatoid arthritis.

Figure 1

Immune factors in osteoclastogenesis. Osteoclasts differentiation from pre-osteoclasts involves several factors, most of which are derived from the immune system. Signaling from TREM2, OSCAR, c-FMS, and RANK cause the nuclear translocation of several transcription factors activating pre-osteoclasst proliferation and differentiation. These include the master osteoclastogenesis controllers NFATc1, which also self-amplifies, and NFkB, along with the early commitment factor PU.1 and AP1. This is enacted both directly by RANK, and indirectly through TRAFs and PLCγ. Osteoclastogenesis can be hindered by several factors, two key ones are the decoy receptor for RANKL, OPG, and the immune factor NUR77, which can inhibit NFATc1 stopping its self-amplifcation loop. The final outcome of these molecular pathways is the transcription of key osteoclast genes, such as DC-STAMP, MMP9. CTSK, ACP5, and RANK, which eventually results in the generation of a mature osteoclast.

Figure 2

Regulation of immune cells by bone cells. Osteoclasts reduce hematopoietic stem cells (HSCs) homing by secreting cathepsin K (CTSK), which in turn degrades stromal cell-derived factor (SDF)1, stem cell factor (SCF), and osteopontin (OPN) depriving the bone niche of HSC-binding sites, which causes their mobilization. Osteoblasts, after stimulation with pro-osteoblastogenic factors such as intermittent parathyroid hormone (PTH), express Jagged1 (Jag1), which binds NOTCH1 on HSCs, and allows them to engraft and survive into the endosteal niche. B cells and bone cells communicate in multiple ways. For example, osteoblasts produce IL-7 and the chemokine CXCL12, that are fundamental for B-cells survival and activity.