Activation of p38 MAPK is a key step in tumor necrosis factor–mediated inflammatory bone destruction

Abstract

Objective. To investigate whether activation of p38 MAPK is a crucial signaling factor in inflammatory bone destruction mediated by tumor necrosis factor (TNF). Mice overexpressing TNF were treated with 2 different inhibitors of p38 MAPK, and the effect of this treatment on joint inflammation and structural damage was assessed.Methods. Human TNF-transgenic mice received systemic treatment with 2 different p38 MAPK inhibitors (RO4399247 and AVE8677). Treatment was started at the time of symptom onset and lasted for 6 weeks. Mice were assessed for clinical signs of arthritis, bone erosion, and cartilage damage. In addition, the effect of these inhibitors on osteoclast generation in vitro and in vivo was assessed.Results. Both p38 MAPK inhibitors significantly reduced clinical signs of TNF-mediated arthritis. This was attributable to reducing synovial inflammation by 50% without affecting the cellular composition of the infiltrate. Synovial expression of interleukin-1 and RANKL was reduced upon p38 MAPK blockade, and activation of the molecular target MAPK-activated protein kinase 2 (MAPKAP-2) was also inhibited. Proteoglycan loss of articular cartilage was reduced by 50%, although p38 MAPK inhibition did not change matrix molecule synthesis by cultivated chondrocytes. Importantly, bone loss was almost completely prevented by p38 MAPK inhibition. The numbers of synovial osteoclasts and precursors were dramatically reduced, and both p38 MAPK inhibitors also inhibited in vitro osteoclastogenesis at micromolar concentrations and blocked activation of MAPKAP-2 as well as differentiation markers in cultured osteoclast precursors.Conclusion. These results suggest the major importance of p38 MAPK for TNF-mediated inflammatory bone destruction in arthritis and suggest that inhibition of p38 MAPK might be an important tool for reducing structural damage in rheumatoid arthritis.

Cathepsins B, K, and L Are Regulated by a Defined Collagen Type II Peptide via Activation of Classical Protein Kinase C and p38 MAP Kinase in Articular Chondrocytes

“…Activation of p38 MAP kinase by various stimuli induces chondrocyte senescence and apoptosis (57)(58)(59), and it plays a role in the maintenance of osteoarthritis (60). Therefore, we tested the impact of Ntelo on signaling events downstream of protein kinase C stimulating catabolic processes by activation of the MAP kinase signaling pathway.…”

Differential regulation of matrix metalloproteinase 2 and matrix metalloproteinase 9 by activated protein C: Relevance to inflammation in rheumatoid arthritis

“…The MAP kinase family member p38 is a major signaling molecule of inflammation and is considered to be one of the most important signals for TNF␣-mediated inflammatory responses (31,32). Inhibitors of p38 have been successfully tested in animal models of arthritis, such as collagen-induced arthritis (32).…”

“…Inhibitors of p38 have been successfully tested in animal models of arthritis, such as collagen-induced arthritis (32). Inhibition of p38 MAP kinase diminishes clinical signs and all major histopathologic features of chronic arthritis, including synovial inflammation, cartilage damage, and bone loss (31). Effective blockade of p38 MAP kinase might therefore be regarded as a therapeutic option for the protection of joints from inflammatory destruction.…”

“…Like NF-B, the MAP kinase family member p38 is one of the major signals for TNF␣-mediated inflammatory responses and plays a critical role in the development and progression of arthritis (31,32). We examined whether p38 was involved in APC-induced MMP-9 inhibition.…”

The α-Isoform of p38 MAPK Specifically Regulates Arthritic Bone Loss

“…For instance, p38␣ was shown to be involved in the protection against LPS-induced liver failure (13), it also mediated proinflammatory and anti-inflammatory responses induced by skin injury (14). p38 are also strongly activated in joints of patients with rheumatoid arthritis (RA) 3 (15) as well as in mouse models of inflammatory arthritis (16). In RA, proinflammatory cytokines such as TNF-␣, IL-1␤, and IL-6 play a decisive role in inflammation but also in structural damage of the affected joints.…”