Irreversible joint destruction is a characteristic feature of RA. TCZ monotherapy for 52 weeks showed significantly less radiographic change in total Sharp score (bone erosion and joint space narrowing) than DMARD treatment [28
As a pathogenic mechanism of bone destruction, osteoclasts activated by inflammatory cytokines are thought to be responsible for focal bone erosion. Indeed, osteoclasts are often seen in the synovium at sites of cartilage destruction in RA patients [29
]. The receptor activator of NF-κ
B (RANK) and its ligand (RANKL) are essential factors for osteoclastogenesis [31
]. IL-6 and sIL-6R, but not IL-6 alone, induced RANKL expression in RA-FLS. On the other hand, TNFα
and IL-17 did not induce RANKL expression, although both stimulate cell growth and IL-6 production. Interestingly, in the presence of sIL-6R, TNFα
or IL-17 induced RANKL expression (). In a coculture of RA-FLS and osteoclast precursor cells, IL-6 and sIL-6R induced NFATc1 and TRAP5b mRNA expression in the osteoclast precursor cells. IL-6/sIL-6R directly induced osteoclastogenesis by inducing RANKL expression in RA-FLS [26
]. Moreover, in mouse calvarial bone cultures, IL-6, in the presence of sIL-6R, induced bone resorption, which was decreased by osteoclast inhibitors, suggesting that IL-6 signaling influences osteoclastogenesis induced by osteoblast and osteoclast interaction [34
]. From these facts, IL-6 induces osteoclast formation by inducing RANKL in RA-FLS as well as osteoblast.
Mechanism of RANKL induction by cytokines.
Cartilage degeneration is also observed in RA joints. RANKL inhibition clearly halted the progression of bone erosion, but did not improve joint space narrowing in RA patients, strongly suggesting that RANKL/RANK signaling does not participate in cartilage degeneration in RA patients [35
]. Matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin-like repeat (ADAMTSs) are thought to play crucial roles in cartilage matrix degeneration. IL-6 induced MMP-1, MMP-3, and MMP-13 production from chondrocytes and synovial cells [36
]. On the other hand, it is reported that tissue inhibitors of MMPs (TIMPs) are endogenous inhibitors of MMPs. IL-6, in the presence of sIL-6R, induced the production of TIMP in cultured human chondrocytes and synovial fibroblasts, suggesting that IL-6 plays a role in extracellular matrix turnover [38
These data suggest that the preventive effect of TCZ on joint destruction is mediated by the inhibition of IL-6-induced RANKL induction followed by osteoclastogenesis and suppression of the IL-6-induced production of MMPs. In the SAMURAI and OPTION studies, improvement in a bone resorption marker (C-terminal cross-linking telopeptide of type I collagen) and in cartilage turnover markers (N-terminal propeptide of type IIA collagen and type II collagen helical peptide) were seen in the TCZ group [28
]. Moreover, tocilizumab decreased serum MMP-3 levels in several clinical trials [40