Temporal differential effects of proinflammatory cytokines on osteoclastogenesis

Abstract

Bone destruction and inflammation are closely linked. Cytokines play an important role in inflammatory bone destruction by upregulating the receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL). The direct role of cytokines that act in a non-RANKL-dependent manner has yet to be elucidated. The aim of this study was to investigate the direct osteoclastogenic properties of inflammatory cytokines at different time-points of osteoclastogenesis. Mouse bone marrow macrophages were stimulated with the macrophage colony-stimulating factor (M-CSF) and various concentrations of RANKL. Inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-17 and IL-23, were added to the culture system of osteoclastogenesis. Two time-points of cytokine treatment were set. The ‘early’ effect of each cytokine was investigated at the time of first RANKL treatment, whereas the ‘late’ effect was investigated 48 h after the first RANKL challenge. Osteoclast differentiation and function were assessed using an osteoclast marker [tartrate-resistant acid phosphatase (TRAP)] and by visualization of pit formation. A permissive level of RANKL was required for cytokine-associated osteoclastogenesis in all experiments. In the M-CSF/RANKL monocellular culture system, IL-1β enhanced and IL-6 decreased osteoclast formation in a dose-dependent manner, regardless of temporal differences. Other cytokines showed various responses according to the phase of osteoclast maturation and the concentration of each cytokine and RANKL. Furthermore, luciferase assays showed that both IL-1β and RANKL activated the NF-κB signaling pathway. Collectively, our data revealed that targeting IL-1β may be a promising strategy to inhibit inflammation-associated bone destruction and osteoporosis.

RETRACTED: Resveratrol rescued the TNF-α-induced impairments of osteogenesis of bone-marrow derived mesenchymal stem cells and inhibited the TNF-α-activated NF-кB signaling pathway

“…Nevertheless, there are some contradictory studies and reports demonstrating that TNF-α may help and promote osteogenic differentiation. Such discrepancy may be due to the concentration and the differentiation state of the cell type used as well as the exposure time [3,5]. TNF-α may also have cross-talk with many other signaling pathways, such as MAPK, Wnt, and TGF-β/BMP signaling during osteogenic differentiation [2,5,8], which may inhibit the growth, proliferation, and differentiation of osteoblasts and their progenitors [2].…”

“…Tumor necrosis factor alpha (TNF-α),apro-inflammatory cytokine, plays a pivotal role in inflammation, for example it may activate the nuclear factor kappa-B (NF-κB) signaling which is involved in inflammation and apoptosis of bone cells [1,3,4]. TNF-α is implicated in different inflammatory bone diseases, for example in rheumatoid arthritis and ankylosing spondylitis [2,3,5]. Previous studies have demonstrated that TNF-α may inhibit osteogenesis of mesenchymal stem cells (MSCs) in bone metabolism through down-regulation of runt-related transcription factor-2 (Runx2), osterix (Osx, also known as SP7), and insulin-like growth factor-1 [2,[5][6][7].…”

“…TNF-α is implicated in different inflammatory bone diseases, for example in rheumatoid arthritis and ankylosing spondylitis [2,3,5]. Previous studies have demonstrated that TNF-α may inhibit osteogenesis of mesenchymal stem cells (MSCs) in bone metabolism through down-regulation of runt-related transcription factor-2 (Runx2), osterix (Osx, also known as SP7), and insulin-like growth factor-1 [2,[5][6][7]. Nevertheless, there are some contradictory studies and reports demonstrating that TNF-α may help and promote osteogenic differentiation.…”

Amiloride inhibits osteoclastogenesis by suppressing nuclear factor-κB and mitogen-activated protein kinase activity in receptor activator of nuclear factor-κB-induced RAW264.7 cells

“…Excessive bone resorption by osteoclasts is observed in certain lytic bone diseases, including osteoporosis, hypercalcemia and rheumatoid arthritis, as well as tumor metastases in the bone, periodontitis and Paget's disease (2,3). Patients with lytic bone diseases are at a higher risk of sustaining fractures.…”

The antibody atliximab attenuates collagen-induced arthritis by neutralizing AIMP1, an inflammatory cytokine that enhances osteoclastogenesis

“…In addition, AIMP1 enhances the expression of intercellular adhesion molecule-1 (ICAM-1) which plays a critical role in lymphocyte extravasation, inflammation and atherosclerosis [17,18,24]. Furthermore, AIMP1 stimulates the maturation of DCs, which induces the expression of IL-1b, IL-6, and IL-12, cytokines critical for sequential immune activation [16,25,26]. IL-1b and IL-6 are known to stimulate osteoclastogenesis [1].…”