Tumor necrosis factor–inhibiting therapy preferentially targets bone destruction but not synovial inflammation in a tumor necrosis factor–driven model of rheumatoid arthritis

Abstract

Objective. To investigate how tumor necrosis factor (TNF)-inhibiting therapy affects bone destruction and inflammation in a TNF-driven mouse model of rheumatoid arthritis.Methods. In order to evaluate the influence of TNF on osteoclastogenesis in vitro, different concentrations of TNF were added to spleen cell-derived monocytes in the absence or presence of different concentrations of RANKL. In addition, the effects of TNF inhibition on osteoclast precursors as well as local bone destruction in vivo were assessed by treating TNFtransgenic mice with different doses of adalimumab.Results. TNF stimulated osteoclastogenesis mainly by increasing the number of osteoclast precursor cells in vitro. This TNF effect was independent of the presence of RANKL. In the hTNF-transgenic mouse model of destructive arthritis, low-dose TNF-inhibiting therapy with adalimumab had no effect on synovial inflammation but significantly inhibited local bone destruction and the generation of osteoclasts. This inhibition was accompanied by a reduction in the number of c-Fms-positive osteoclast precursor cells in the bone marrow and a reduction of the osteoclast precursor pools in the blood and inflamed synovial membrane of hTNF-transgenic mice. Conclusion. Low-dose TNF-inhibiting therapy significantly reduces bone erosions by reducing the number of circulating and joint-invading osteoclast precursors. This effect is uncoupled from its antiinflammatory action.Proinflammatory cytokines play an important pathogenetic role in rheumatoid arthritis (RA). In particular, tumor necrosis factor (TNF) can elicit the whole inflammatory cascade, leading to the typical joint swelling and subsequent structural joint damage characteristic of the disease (1). Moreover, mice overexpressing TNF exhibit a severe inflammatory and rapidly destructive arthritis (2). Joint destruction involves both cartilage degradation and erosions of juxtaarticular bone. The latter is mediated by osteoclasts (OCs) (3,4), a cell population derived from the monocyte/ macrophage lineage. Osteoclast formation requires the presence of macrophage colony-stimulating factor (M-CSF) in the early stages of development and involves the formation of mononuclear tartrate-resistant acid phosphatase (TRAP)-positive OC precursor cells (pre-OCs) as an intermediary step (5). Although OC differentiation, maturation, and activation are pivotally dependent on the availability of RANKL and its receptor RANK (5-7), TNF can amplify osteoclastogenesis in the presence (and possibly even in the absence) of RANKL

Activated Protein C Inhibits Proliferation and Tumor Necrosis Factor α-Stimulated Activation of p38, c-Jun NH2-Terminal Kinase (JNK) and Akt in Rheumatoid Synovial Fibroblasts

“…In agreement, IL-1β, but not TNFα, significantly stimulates ERK activation in human RSFs and rabbit synovial fibroblasts (51,52). Nonetheless, the effect of TNFα on RA inflammation appears to be dose-dependent (53), and when used in vitro at considerably higher doses (15-50 ng/mL) than the current study, TNFα can stimulate ERK activation (54,55). Anti-TNFα treatment can prevent RA joint destruction without affecting the clinical signs and symptoms of inflammation (56)(57)(58).…”

Multifaceted role of TNF-α during the pathogenesis of rheumatoid arthritis

“…These data suggest that antiresorptive activity of TNF-α was not affected at lower concentration but not synovial inflammation. Taken together Binder et al [18] exemplified the need of controlling both cartilage destruction as well as inflammation mediated by TNF-α during the treatment of rheumatoid arthritis.…”

“…Nonetheless, the mechanism of the biphasic effect of biological TNF-α inhibitors was not yet fully understood. Therefore, Binder et al [18] investigated the fundamental mechanism of TNF-α during RA by in vitro studies and human TNF-α (hTNF) transgenic destructive arthritis mouse model. The authors have chosen monocytes derived from spleen cells and tested the osteoclastogenesis in vitro us-ing different concentrations of TNF-α inhibitor adalimumab and activator RANKL.…”

The immune system and postmenopausal osteoporosis

“…A key role of T cell-produced TNF has been demonstrated in post-menopausal osteoporosis (D'Amelio et al, 2008) and in other condition as rheumatoid arthritis (Binder et al, 2013;Diarra et al, 2007;Takahata et al, 2012), multiple myeloma Kawano et al, 2011), and bone metastasis (Das Roy et al, 2009;Roato et al, 2005;Roato et al, 2008). The effect of TNF on osteoclastogenesis is up-regulated by IL-1 (Wei et al, 2005), this cytokine enhances RANKL expression by bone marrow stromal cells and directly promotes OCs differentiation.…”