Rheumatoid Arthritis in the View of Osteoimmunology

Abstract

Rheumatoid arthritis is characterized by synovial inflammation and irreversible bone erosions, both highlighting the immense reciprocal relationship between the immune and bone systems, designed osteoimmunology two decades ago. Osteoclast-mediated resorption at the interface between synovium and bone is responsible for the articular bone erosions. The main triggers of this local bone resorption are autoantibodies directed against citrullinated proteins, as well as pro-inflammatory cytokines and the receptor activator of nuclear factor-κB ligand, that regulate both the formation and activity of the osteoclast, as well as immune cell functions. In addition, local bone loss is due to the suppression of osteoblast-mediated bone formation and repair by inflammatory cytokines. Similarly, inflammation affects systemic bone remodeling in rheumatoid arthritis with the net increase in bone resorption, leading to systemic osteoporosis. This review summarizes the substantial progress that has been made in understanding the pathophysiology of systemic and local bone loss in rheumatoid arthritis.

Keywords: bone erosion; inflammatory bone loss; osteoclast; rheumatoid arthritis.

Figure 1

Bone erosions of the foot in rheumatoid arthritis (RA). Arrows show erosions on metacarpophalangeal joints.

Figure 2

Synovial membrane and bone interactions in rheumatoid arthritis. The inflamed synovium produces inflammatory mediators that enhance osteoclastogenesis, mostly by the upregulation of the receptor activator of NF-κB ligand (RANKL), leading to articular bone erosions development. In addition, osteoclasts as well as their precursors can be directly activated by anti-citrullinated protein antibodies (ACPAs) present long before during the pre-clinical phase of the disease. Osteoblast differentiation, on the other hand, is inhibited by antagonists of the Wnt signaling pathway, including Dickkopf (DKK-1) and sclerostin, preventing erosion repair. ACPA: Anti-citrullinated peptide antibodies; ATX: Autotaxin; DKK-1: Dickkopf related protein 1; IFN: Interferon; IL: Interleukine; LPA: Lysophosphatidic acid; LPC: Lysophosphatidylcholine; M-CSF: Macrophage colony-stimulating factor; OPG: Osteoprotegerin; RANK: Receptor activator of nuclear factor kappa B; RANKL: RANK ligand; TNF: Tumor necrosis factor; Th: T-cell; dashed triangle arrowheads: Secretion; simple triangle arrowheads: Chemical reaction; round arrowheads: Activation; flat arrowheads: Inhibition.

Figure 3

Enhanced osteoclast bone resorption in rheumatoid arthritis. Bone resorption is mediated by multiple pathways (RANKL/RANK, inflammatory cytokines, ITAM/Ca²⁺, and ATX/LPA) converging on NFATc1. Additionally, bone loss is mediated by direct and indirect ACPA-related mechanisms. ACPA: Anti-citrullinated peptide antibodies; ATX: Autotaxin; BLNK: B-cell linker protein; BtK: Burton tyrosine kinase; CD: Cluster of differentiation; CTLA4: Cytotoxic T-lymphocyte-associated protein 4; DAP-12: DNAX-activating protein of 12 kDa; Enpp2: Ectonucleotid pyrophosphatase/phosphodiesterase 2; FcγR: Fc gamma receptor; FcRγ: Fc receptor gamma subunit; IgG: Immunoglobulin G; IL: Interleukine; LPA: Lysophosphatidic acid; LPAR: LPA receptor; LPC: Lysophosphatidylcholine; MHC-1: Major histocompatibility complex 1; NFATc1: Nuclear factor of activated T-cells cytoplasmic 1; NF-κb: Nuclear factor kappa B; OSCAR: Osteoclast associated receptor; PLCγ: Phospholipase C gamma; RANK: Receptor activator of nuclear factor kappa B; RANKL: RANK ligand; Syk: Spleen tyrosine kinase; TNF: Tumor necrosis factor; TRAF6: TNF receptor-associated factor 6; TREM-2: Triggering receptor expressed on myeloid cell. 2. Dashed triangle arrowheads: Secretion; simple triangle arrowheads: Chemical reaction; round arrowheads: Activation; flat arrowheads: Inhibition.