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Histamine contributes to increased RANKL/OPG ratio through altered NR4A activity in human chondrocyte cells.
MedLine Citation:
PMID:  22674155     Owner:  NLM     Status:  Publisher    
OBJECTIVE: To elucidate histamine receptor-mediated signaling pathways, transcriptional events and target gene expression in human cartilage. METHODS: Histamine modulation of cartilage destruction was assessed by Safranin-O staining and proteoglycan release (n=6). Histamine receptor (HR1,-2,-3,-4) dependent regulation of transcription factors (NR4A1,-2,-3), the receptor activator for NF-κB-ligand (RANKL) and osteoprotegerin (OPG) mRNA levels were measured in primary (n=8) and SW-1353 chondrocyte cells using qPCR and selective HR antagonists. sRANKL and OPG protein levels were determined using ELISAs. NR4A protein levels and transactivity were evaluated by western, immunocytochemistry and luciferase reporter assays. Stable depletion of NR4A1-3 was achieved by lentiviral transduction of NR4A shRNA. RESULTS: Primary human chondrocyte cells express differential steady state levels of HR1-4 mRNA. In combination with TNFα, histamine significantly promotes cartilage proteoglycan depletion and release. Histamine, in a time- and concentration-dependent fashion, modulates expression of NR4A1-3 orphan receptors in primary and immortalized human chondrocyte cells. Histamine selectively signals through HR1 and HR2 in chondrocytes to modulate RANKL and NR4A2 expression. The temporal effects of histamine on NR4A2 gene transcription are reduced in cells pre-treated with inhibitors directed against PKA, MAPK and NF-κB signaling pathways. Histamine modulates the expression of RANKL with modest effects on OPG levels, leading to increased RANKL/OPG mRNA and protein ratios. Stable knockdown of NR4A1-3 expression results in reduced endogenous OPG levels and the loss of histamine-dependent regulation of RANKL expression. CONCLUSION.: Histamine, via HR1 and HR2, contributes to joint disease by enhancing the RANKL/OPG expression ratio through altered NR4A activity in human chondrocyte cells.
Viviana Marzaioli; Jason P McMorrow; Hannes Angerer; Alyssa Gilmore; Daniel Crean; Davide Zocco; Peadar Rooney; Douglas Veale; Ursula Fearon; Martina Gogarty; Alice N McEvoy; Martin H Stradner; Evelyn P Murphy
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-6-5
Journal Detail:
Title:  Arthritis and rheumatism     Volume:  -     ISSN:  1529-0131     ISO Abbreviation:  -     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-6-7     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0370605     Medline TA:  Arthritis Rheum     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 by the American College of Rheumatology.
UCD Veterinary Sciences Centre and Conway Institute for Biomolecular and Biomedical Research, University College Dublin.
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