PMID- 12384922
OWN - NLM
STAT- MEDLINE
DCOM- 20021114
LR  - 20131121
IS  - 0004-3591 (Print)
IS  - 0004-3591 (Linking)
VI  - 46
IP  - 10
DP  - 2002 Oct
TI  - The in situ up-regulation of chondrocyte interleukin-1-converting enzyme and 
      interleukin-18 levels in experimental osteoarthritis is mediated by nitric oxide.
PG  - 2637-47
AB  - OBJECTIVE: To investigate in situ the relationship between 2 key mediators 
      implicated in osteoarthritic (OA) cartilage: nitric oxide (NO) and 
      interleukin-1-converting enzyme (ICE). Interleukin-18 (IL-18) was also studied 
      and served as reference for the effects of ICE. METHODS: An OA model was created 
      in dogs by sectioning (stab wound) the anterior cruciate ligament of the right 
      stifle joint. Three experimental groups were studied: unoperated untreated dogs, 
      operated untreated dogs (OA), and OA dogs treated with oral N-iminoethyl-L-lysine 
      (L-NIL), a specific inhibitor of inducible nitric oxide synthase (iNOS) (10 mg/kg 
      twice a day starting immediately after surgery). At 12 weeks after surgery, 
      cartilage from the femoral condyles and tibial plateaus were processed for 
      immunohistochemistry for ICE, IL-18, and protease inhibitor 9 (PI-9), a natural 
      inhibitor of ICE, followed by morphometric analysis. Cartilage specimens from the 
      femoral condyles of untreated OA dogs were dissected and incubated with specific 
      inhibitors of different signaling pathways likely to be involved in the OA 
      process: SB 202190 (10 microM; a p38 mitogen-activated protein kinase [MAPK] 
      inhibitor), PD 98059 (100 microM; a MAPK kinase 1/2 [MEK-1/2] inhibitor), NS-398 
      (10 ng/ml; a specific cyclooxygenase 2 [COX-2] inhibitor), and L-NIL (50 microM). 
      RESULTS: Both ICE and IL-18 were present in situ in the canine cartilage, with a 
      significant increase in the level of these 2 proteins in OA cartilage. In 
      contrast, the level of PI-9 was lower in OA than in normal cartilage (difference 
      not statistically significant). Compared with untreated OA cartilage, oral 
      treatment with L-NIL significantly decreased ICE and IL-18 levels in cartilage 
      from the femoral condyles and tibial plateaus, to values similar to those in 
      normal dogs. L-NIL also increased the PI-9 level in normal dogs compared with OA 
      dogs, reaching statistical significance for femoral condyle cartilage. 
      Interestingly, in vitro experiments demonstrated significant inhibition of ICE 
      levels by p38, MEK-1/2, and COX-2 inhibitors, but not by the iNOS inhibitor. 
      CONCLUSION: This study demonstrated that in situ in OA cartilage, the stimulation 
      of chondrocytes by NO is at least partly responsible for the up-regulation of ICE 
      and IL-18 synthesis while decreasing the level of the ICE inhibitor PI-9. The ICE 
      level is controlled by the activation of at least 2 MAPK pathways, p38 and 
      MEK-1/2. Interestingly, it appears that ICE synthesis is not regulated by the 
      endogenous production of NO. These data highlight the role played by iNOS in 
      regulating the synthesis of major catabolic factors involved in OA cartilage 
      degradation.
FAU - Boileau, Christelle
AU  - Boileau C
AD  - Osteoarthritis Research Unit, Hopital Notre-Dame, Centre hospitalier de 
      l'Universite de Montreal, 1560 rue Sherbrooke East, Montreal, Quebec H2L 4M1, 
      Canada.
FAU - Martel-Pelletier, Johanne
AU  - Martel-Pelletier J
FAU - Moldovan, Florina
AU  - Moldovan F
FAU - Jouzeau, Jean-Yves
AU  - Jouzeau JY
FAU - Netter, Patrick
AU  - Netter P
FAU - Manning, Pamela T
AU  - Manning PT
FAU - Pelletier, Jean-Pierre
AU  - Pelletier JP
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Arthritis Rheum
JT  - Arthritis and rheumatism
JID - 0370605
RN  - 0 (Interleukin-18)
RN  - 0 (SERPINB9 protein, human)
RN  - 0 (Serpins)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - EC 3.4.22.36 (Caspase 1)
SB  - IM
MH  - Animals
MH  - Cartilage/metabolism
MH  - Caspase 1/*metabolism
MH  - Chondrocytes/*enzymology
MH  - Dogs
MH  - Enzyme Activation/physiology
MH  - Interleukin-18/*metabolism
MH  - Nitric Oxide/*metabolism
MH  - Nitric Oxide Synthase/metabolism
MH  - Nitric Oxide Synthase Type II
MH  - Osteoarthritis/*metabolism
MH  - Serpins/metabolism
MH  - Up-Regulation/physiology
EDAT- 2002/10/18 04:00
MHDA- 2002/11/26 04:00
CRDT- 2002/10/18 04:00
PHST- 2002/10/18 04:00 [pubmed]
PHST- 2002/11/26 04:00 [medline]
PHST- 2002/10/18 04:00 [entrez]
AID - 10.1002/art.10518 [doi]
PST - ppublish
SO  - Arthritis Rheum. 2002 Oct;46(10):2637-47. doi: 10.1002/art.10518.