ArticleJournal of orthopaedic research : official publication of the Orthopaedic Research Society2012
Lysine392, a K63-linked ubiquitination site in NEMO, mediates inflammatory osteoclastogenesis and osteolysis.
Article in Journal of orthopaedic research : official publication of the Orthopaedic Research Society, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 12 citations in OpenAlex.
- NF-κB/RelA signaling required for CD40-induced humoral immunity depends on specific NEMO lysine residues in mice.The EMBO journal · 2026Article
- TRIMs: selective recruitment at different steps of the NF-κB pathway-determinant of activation or resolution of inflammation.Cellular and molecular life sciences : CMLS · 2021Review
- PARP1 Hinders Histone H2B Occupancy at the NFATc1 Promoter to Restrain Osteoclast Differentiation.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2020Article
- Inflammatory osteolysis is regulated by site-specific ISGylation of the scaffold protein NEMO.eLife · 2020Article
- Osteoclasts-Key Players in Skeletal Health and Disease.Microbiology spectrum · 2016Review
- Poly-ADP-ribosylation-mediated degradation of ARTD1 by the NLRP3 inflammasome is a prerequisite for osteoclast maturation.Cell death & disease · 2016Article
- NF-κB decoy oligodeoxynucleotide inhibits wear particle-induced inflammation in a murine calvarial model.Journal of biomedical materials research. Part A · 2015Article
- Innate immunity sensors participating in pathophysiology of joint diseases: a brief overview.Journal of long-term effects of medical implants · 2014Article
- NF-κB signaling and bone resorption.Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA · 2013Review
- Ubiquitin-like domain of IKKβ regulates osteoclastogenesis and osteolysis.Calcified tissue international · 2013Article
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
PMMA particles released from bone implants are considered major contributor to osteolysis and subsequent implant failure. Although the ensuing inflammatory response has been described, the mechanisms underlying PMMA particulate-induced osteolysis remain enigmatic. In previous studies, we have established that activation of Nuclear factor kappa-B (NF-κB) and MAP kinase pathways plays a central role in the pathogenesis of inflammatory osteolysis. Specifically, we have shown that impeding IKK complex assembly, and thus subsequent NF-κB activation, dampens particle-induced osteolysis. The IKK complex consists of IKKα, IKKβ, and IKKγ, also known as NEMO. NEMO has no catalytic activity and serves as a scaffold protein facilitating assembly and distal activation of NF-κB signaling. In fact, blocking binding of NEMO with IKKα/β abolishes NF-κB activity. In the current study, we identify Lysine 392 residue in NEMO as crucial mediator of PMMA particle-induced inflammatory osteoclastogenesis and osteolysis. Using mice in which NEMO-K392R mutation has been introduced, we provide evidence that PMMA-induced osteoclasts and osteolytic responses are impaired. Furthermore, we show that this impairment is likely due to poor activation of NF-κB and Erk, but not other MAP kinases. Our findings suggest that NEMO Lysine392, a well-established K63-linked polyubiquitination site, is an important mediator of PMMA-induced osteolysis. Therefore, this NEMO motif should be considered as a target to combat PMMA particle-induced osteolysis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.