Document Detail


NF-kappaB signaling: multiple angles to target OA.
MedLine Citation:
PMID:  20199390     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In the context of OA disease, NF-kappaB transcription factors can be triggered by a host of stress-related stimuli including pro-inflammatory cytokines, excessive mechanical stress and ECM degradation products. Activated NF-kappaB regulates the expression of many cytokines and chemokines, adhesion molecules, inflammatory mediators, and several matrix degrading enzymes. NF-kappaB also influences the regulated accumulation and remodeling of ECM proteins and has indirect positive effects on downstream regulators of terminal chondrocyte differentiation (including beta-catenin and Runx2). Although driven partly by pro-inflammatory and stress-related factors, OA pathogenesis also involves a "loss of maturational arrest" that inappropriately pushes chondrocytes towards a more differentiated, hypertrophic-like state. Growing evidence points to NF-kappaB signaling as not only playing a central role in the pro-inflammatory stress-related responses of chondrocytes to extra- and intra-cellular insults, but also in the control of their differentiation program. Thus unlike other signaling pathways the NF-kappaB activating kinases are potential therapeutic OA targets for multiple reasons. Targeted strategies to prevent unwanted NF-kappaB activation in this context, which do not cause side effects on other proteins or signaling pathways, need to be focused on the use of highly specific drug modalities, siRNAs or other biological inhibitors that are targeted to the activating NF-kappaB kinases IKKalpha or IKKbeta or specific activating canonical NF-kappaB subunits. However, work remains in its infancy to evaluate the effects of efficacious, targeted NF-kappaB inhibitors in animal models of OA disease in vivo and to also target these strategies only to affected cartilage and joints to avoid other undesirable systemic effects.
Authors:
Kenneth B Marcu; Miguel Otero; Eleonora Olivotto; Rosa Maria Borzi; Mary B Goldring
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  Current drug targets     Volume:  11     ISSN:  1873-5592     ISO Abbreviation:  Curr Drug Targets     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-03-31     Completed Date:  2010-06-17     Revised Date:  2013-05-30    
Medline Journal Info:
Nlm Unique ID:  100960531     Medline TA:  Curr Drug Targets     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  599-613     Citation Subset:  IM    
Affiliation:
Biochemistry and Cell Biology Department, Stony Brook University, Stony Brook, NY 11794, USA. kenneth.marcu@stonybrook.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Anti-Inflammatory Agents / pharmacology*,  therapeutic use
Cell Differentiation / drug effects
Chondrocytes / metabolism
Drug Delivery Systems / methods*
Humans
I-kappa B Kinase / antagonists & inhibitors
Models, Biological
NF-kappa B / antagonists & inhibitors*,  metabolism
Osteoarthritis / drug therapy*,  metabolism
Signal Transduction / drug effects*
Grant Support
ID/Acronym/Agency:
AG022021/AG/NIA NIH HHS; GM066882/GM/NIGMS NIH HHS; R01 AG022021-08/AG/NIA NIH HHS; R01 GM066882-04/GM/NIGMS NIH HHS; R21-AR054887/AR/NIAMS NIH HHS; RC4 AR060546-01/AR/NIAMS NIH HHS
Chemical
Reg. No./Substance:
0/Anti-Inflammatory Agents; 0/NF-kappa B; EC 2.7.11.10/I-kappa B Kinase
Comments/Corrections

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