Regulation of osteoclast activation and inflammation signal transduction in inflammatory arthritis
Date Issued
2015
Date
2015
Author(s)
Liao, Hsiu-Jung
Abstract
Osteoclasts are bone resorbing multinucleated cells involves interactions between tumor necrosis factor (TNF) ligand superfamily members and their receptors. Accumulated evidences indicate that the signaling mechanism of RANKL in promoting osteoclasteogenesis has been extensively studied. RANKL activates TRAF6 signaling pathways, which are indispensable for the induction and activation of osteoclast differentiation. In previous study, our results have demonstrated that TRAIL induces osteoclast differentiation via a TRAF-6-dependent signaling pathway. Interestingly, our results also demonstrated that TRAIL suppressed osteoclastic differentiation induced by RANKL plus M-CSF. Therefore, TRAIL can both promote and suppress osteoclast differentiation, depending on the presence of RANKL or other TNF superfamily molecules, suggesting that TRAIL may play a role in regulating osteoclast differentiation in osteoimmunology. It is possible that the regulation is at the lipid raft and TRAF6 associated signaling. Membrane lipid rafts play a key role in immune cell activation by recruiting and excluding specific signaling components of immune cell surface receptors upon the receptor engagement. We demonstrated that rafts in osteoclasts may function as the platform for a network of signaling molecules that assemble in response to RANKL. TRAIL blocked osteoclastic differentiation was accompanied by interference the RANK signaling required the function of raft membrane microdomains. Furthermore, in collagen-induced arthritis rat animal model, treatment with TRAIL not only the improved the bone density and inhibited bone erosion, but also reduced the joint swelling and inflammation. However, the anti-inflammation effects of TRAIL inhibited T cell activation instead of increased apoptosis in T cells. Therefore, TRAIL administration is an effective anti-inflammatory treatment that prevents the development and progression of experimental arthritis. It may provide a potential and new therapeutic strategy of treatment in arthritis. PSTPIP2 is involved in macrophage activation, neutrophil motility, and osteoclast differentiation. However, the role of PSTPIP2 in autoinflammation and osteoclastogenesis is still not clear. In our study, we generated PSTPIP2 knockout (Pstpip2-/-) mice to investigate its phenotype and role in autoinflammatory diseases. All Pstpip2-/- mice developed paw swelling, synovitis, hyperostosis, and osteitis, resembling SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis), an inflammatory disorder of the bone, skin, and joints. Multifocal osteomyelitis was found in inflamed paws with increased macrophage and marked neutrophil infiltrations in the bone, joint, and skin. Profound osteolytic lesions with marked decreased bone volume density developed in paws and limbs. Neutrophil-attracting chemokines and IL-1s were markedly elevated in inflamed tissues. Our study suggests that PSTPIP2 could play a role in innate immunity and development of osteoclastogenesis in autoinflammatory bone disorders, and may associate with the pathogenesis of human SAPHO syndrome. Taken together, we demonstrated that both TRAIL and PSTPIP2 is involved in osteoclast activation and inflammation, suggesting the cross-talk between signaling transduction pathways in osteoclast activation and inflammation. Understanding of the regulation of these pathways is important to explore the critical steps in oseoimmunology, and help to development of new therapeutic approach in inflammatory arthritis and bone destruction.
Subjects
Osteoclast
TRAIL
Arthritis
SDGs
Type
thesis
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