Positive regulators of osteoclastogenesis and bone resorption in rheumatoid arthritis

Abstract

Bone destruction is a frequent and clinically serious event in patients with rheumatoid arthritis (RA). Local joint destruction can cause joint instability and often necessitates reconstructive or replacement surgery. Moreover, inflammation-induced systemic bone loss is associated with an increased fracture risk. Bone resorption is a well-controlled process that is dependent on the differentiation of monocytes to bone-resorbing osteoclasts. Infiltrating as well as resident synovial cells, such as T cells, monocytes and synovial fibroblasts, have been identified as sources of osteoclast differentiation signals in RA patients. Pro-inflammatory cytokines are amongst the most important mechanisms driving this process. In particular, macrophage colony-stimulating factor, RANKL, TNF, IL-1 and IL-17 may play dominant roles in the pathogenesis of arthritis-associated bone loss. These cytokines activate different intracellular pathways to initiate osteoclast differentiation. Thus, over the past years several promising targets for the treatment of arthritic bone destruction have been defined.

Figure 1

Cytokines activating osteoclastogenesis in rheumatoid arthritis. TNF, IL-1, IL-6 and IL-17 upregulate expression of RANKL (receptor activator of NF-kB ligand) in osteoblasts and synovial fibroblasts. RANKL mediates differentiation, survival and activation of osteoclasts. TNF, produced by fibroblasts and macrophages, promotes differentiation and survival of osteoclasts. IL-1 supports differentiation, survival and activation of osteoclasts. IL-6 and IL-17 promote osteoclastogenesis indirectly. IL-6 is largely produced by fibroblasts and macrophages; it enhances the expression of RANKL and contributes to the induction of Th17 cells. Th17 cells secrete IL-17, but a main source of synovial IL-17 is probably mast cells. IL-17 induces the expression of RANKL in osteoblasts and fibroblasts and enhances secretion of pro-inflammatory cytokines by macrophages. Macrophage colony-stimulating factor (M-CSF) and IL-34 promote differentiation and activation of osteoclasts; IL-33 supports osteoclast differentiation. TGF, transforming growth factor.

Figure 2

Intracellular signalling during inflammation-induced osteoclastogenesis. RANKL (receptor activator of NF-kB ligand) binds to its receptor RANK and induces the key regulator of osteoclast differentiation NFATc1 (Nuclear factor of activated T cells, cytoplasmic 1) through two different signalling pathways. On the one hand, RANK recruits TRAF6 (TNF receptor-associated factor 6) and activates NF-κB, JNK, p38, c-fos and AP-1. On the other hand, NFATc1 is activated by calcineurin that is in turn activated by elevated calcium in the cytoplasm. Phospholipase C (PLC)γ mediates the release of calcium in the cytoplasm; PLCγ is activated by RANK through Btk/Tec and by OSCAR (osteoclast-associated receptor) and TREM-2 (triggering receptor expressed by myeloid cells 2) through the Fc receptor gamma chain (FcRγ), DAP12 (DNAX-activating protein of 12 kDa) and Syk signalling. TNF binds to its receptor TNFR1, which recruits TRADD (TNFR-associated DD protein) and RIP-1 (Receptor interacting protein-1). TNF receptor-associated factor (TRAF)2, TRAF5 and TRAF6 mediate further signalling through NF-κB, JNK and p38. The IL-1 receptor IL-1R1 binds MYD88 (myeloid differentiation primary response gene 88) and RAK4, which activates TRAF6 through phosphorylation of IL-1 receptor-activating protein kinase (IRAK)2 and IRAK1. After binding IL-6, the IL-6 receptor recruits two gp130 molecules and activates the signal transducer and activator of transcription (STAT) pathway and the mitogen-activated protein kinase (MAPK) pathway (JNK, p38, ERK) through gp130. MMP, matrix metalloproteinase.