PMID- 18302237
OWN - NLM
STAT- MEDLINE
DCOM- 20080708
LR  - 20220410
IS  - 1554-527X (Electronic)
IS  - 0736-0266 (Linking)
VI  - 26
IP  - 7
DP  - 2008 Jul
TI  - p38 MAPK inhibition modulates rabbit nucleus pulposus cell response to IL-1.
PG  - 991-8
LID - 10.1002/jor.20604 [doi]
AB  - Analysis of disc gene expression implicated IL-1 in the development of 
      intervertebral disc degeneration (IDD) in a rabbit stab model. The purpose of 
      these studies is to determine the role of p38 Mitogen Activated Protein Kinase 
      (p38 MAPK) signaling in nucleus pulposus cell response to IL-1, and to compare 
      rabbit nucleus pulposus (rNP) cell responses to IL-1 activation with those in a 
      stab model of disc degeneration. NP cells maintained in alginate bead culture 
      were exposed to IL-1, with or without p38 MAPK inhibition. RNA was isolated for 
      reverse transcription polymerase chain reaction (RT-PCR) analysis of gene 
      expression, conditioned media analyzed for accumulation of nitric oxide (NO) and 
      prostaglandin E-2 (PGE-2), and proteoglycan synthesis measured after 10 days. 
      IL-1 upregulation of mRNA for cycloxygenase-2 (COX-2), matrix metalloproteinase-3 
      (MMP-3), IL-1, and IL-6, was blunted by p38 inhibition while downregulation of 
      matrix proteins (collagen I, collagen II, aggrecan) and 
      insulin-like-growth-factor I (IFG-1) was also reversed. mRNA for tissue inhibitor 
      of matrixmetalloproteinase-1 (TIMP-1) was modestly increased by IL-1, while those 
      for Transforming Growth Factor-beta (TGF-beta) SOX-9, and versican remained 
      unchanged. Blocking p38 MAPK reduced IL-1 induced NO and PGE-2 accumulation and 
      partially restored proteoglycan synthesis. p38 MAPK inhibition in control cells 
      increased mRNA for matrix proteins (aggrecan, collagen II, versican, collagen I) 
      and anabolic factors (IGF-1, TGF, and SOX-9) from 50% to 120%, decreased basal 
      PGE-2 accumulation, but had no effect on message for TIMP-1, MMP-3, or COX-2. 
      Inhibition of p38 MAPK in cytokine-activated disc cells blunts gene expression 
      and production of factors associated with inflammation, pain, and disc matrix 
      catabolism while reversing IL-1 downregulation of matrix protein gene expression 
      and proteoglycan synthesis. The results support the hypothesis that IL-1 could be 
      responsible for many of the mRNA changes seen in rabbit NP in the stab model of 
      disc degeneration, and uphold the concept that development of molecular 
      techniques to block p38 MAPK could provide a therapeutic approach to slow the 
      course of intervertebral disc degeneration.
FAU - Studer, Rebecca K
AU  - Studer RK
AD  - VAPHS, 151-U, 2W-144, University Drive C, Pittsburgh, Pennsylvania 15240, USA. 
      rebecca.studer@med.va.gov
FAU - Gilbertson, Lars G
AU  - Gilbertson LG
FAU - Georgescu, Helga
AU  - Georgescu H
FAU - Sowa, Gwendolyn
AU  - Sowa G
FAU - Vo, Nam
AU  - Vo N
FAU - Kang, James D
AU  - Kang JD
LA  - eng
GR  - R21 AR051514/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - J Orthop Res
JT  - Journal of orthopaedic research : official publication of the Orthopaedic 
      Research Society
JID - 8404726
RN  - 0 (Cytokines)
RN  - 0 (Imidazoles)
RN  - 0 (Interleukin-1)
RN  - 0 (Proteoglycans)
RN  - 0 (Pyridines)
RN  - 0 (RNA, Messenger)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - K7Q1JQR04M (Dinoprostone)
RN  - PVX798P8GI (4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Cytokines/metabolism
MH  - Dinoprostone/metabolism
MH  - Disease Models, Animal
MH  - Gene Expression/drug effects
MH  - Imidazoles/pharmacology
MH  - Interleukin-1/*metabolism
MH  - Intervertebral Disc/*metabolism
MH  - Nitric Oxide/metabolism
MH  - Proteoglycans/biosynthesis
MH  - Pyridines/pharmacology
MH  - RNA, Messenger/metabolism
MH  - Rabbits
MH  - Signal Transduction/physiology
MH  - Spinal Diseases/*metabolism
MH  - p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolism
EDAT- 2008/02/28 09:00
MHDA- 2008/07/09 09:00
CRDT- 2008/02/28 09:00
PHST- 2008/02/28 09:00 [pubmed]
PHST- 2008/07/09 09:00 [medline]
PHST- 2008/02/28 09:00 [entrez]
AID - 10.1002/jor.20604 [doi]
PST - ppublish
SO  - J Orthop Res. 2008 Jul;26(7):991-8. doi: 10.1002/jor.20604.