NF-kappaB modulators in osteolytic bone diseases.
Osteoclasts are responsible for bone resorption and play a pivotal role in the pathogenesis of osteolytic disorders. NF-kappaB is a set of nuclear factors that bind to consensus DNA sequences called kappaB sites, and is essential for osteoclast formation and survival. NF-kappaB signalling pathways are strictly regulated to maintain bone homeostasis by cytokines such as RANKL, TNF-alpha and IL-1, which differentially regulate classical and/or alternative NF-kappaB pathways in osteoclastic cells. These pathways are also modulated by NF-kappaB mediators, including TRAF6, aPKC, p62/SQSTM1 and deubiquitinating enzyme CYLD that are involved in the ubiquitin-proteasome system during RANK-mediated osteoclastogenesis. Abnormal activation of NF-kappaB signalling in osteoclasts has been associated with excessive osteoclastic activity, and frequently observed in osteolytic conditions, including periprosthetic osteolysis, arthritis, Paget's disease of bone, and periodontitis. NF-kappaB modulators such as parthenolide and NEMO-binding domain peptide demonstrate therapeutic effects on inflammation-induced bone destruction in mouse models. Unravelling the structure and function of NF-kappaB pathways in osteoclasts and other cell types will be important in developing new strategies for treatments of bone diseases.
Xu
Jiake
J
Centre for Orthopaedic Research, School of Surgery, University of Western Australia, Nedlands, Australia. jiake.xu@uwa.edu.au
Wu
Hua Fei
HF
Ang
Estabelle S M
ES
Yip
Kirk
K
Woloszyn
Magdalene
M
Zheng
Ming H
MH
Tan
Ren Xiang
RX
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation; D051379:Mice; D008954:Models, Biological; D008956:Models, Chemical; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D010003:Osteoarthritis / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D010518:Periodontitis / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction
D016328:NF-kappa B; D004247:DNA