Linked Life Data

19358841

Source:http://linkedlifedata.com/resource/pubmed/id/19358841

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1-3
pubmed:dateCreated
2009-6-1
pubmed:abstractText
Cathepsin K (EC 3.4.22.38) is expressed by osteoclasts and synovial fibroblasts and its proteolytic activity is hypothesized to play a role in the pathology of rheumatoid arthritis. This study explored the effects of the cathepsin K inhibitor N-(1-{[(Cyanomethyl)amino]carbonyl}cyclohexyl)-4-[2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]benzamide (L-006235) in murine collagen-induced arthritis. L-006235 is a potent inhibitor of recombinant human and murine cathepsin K, enzymes (K(i):0.073 nM and IC(50): 2.4 nM, respectively) and at the cellular level in human osteoclasts (IC(50): 28 nM) with ~1000-fold selectivity against cathepsin S. L-006235 did not result in splenic invariant chain p10 accumulation, a specific marker of cathepsin S inhibition. L-006235 was dosed daily (25 mg/kg, p.o.), either prophylactically (days 0-42) or therapeutically (14 days post onset of disease) to DBA/1J mice subjected to collagen-induced arthritis. Disease severity was scored during the course of the study. Histological evaluation of cartilage and bone degradation together with related biomarkers namely, deoxypyridinoline, cartilage oligomeric matrix protein and C-terminal telopeptide degradation product of type I collagen (CTX-I) were analyzed after the study. After prophylactic or therapeutic administration, L-006235 significantly reduced biomarkers reflecting bone and cartilage degradation. Pathological changes at the histological level were significantly reduced after prophylactic treatment (P<0.01), but not after therapeutic treatment. Prophylactic treatment with L-006235 delayed disease onset (P<0.01) and reduced the disease severity score (P<0.05). Inhibition of cathepsin K activity exerts beneficial effects on collagen-induced arthritis in mice and thus warrants further investigation as a therapeutic intervention in human rheumatoid arthritis.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1879-0712
pubmed:author
pubmed:issnType
Electronic
pubmed:day
24
pubmed:volume
613
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
155-62
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed:year
2009
pubmed:articleTitle
Inhibition of cathepsin K reduces bone erosion, cartilage degradation and inflammation evoked by collagen-induced arthritis in mice.
pubmed:affiliation
Karolinska Institutet, Department of Medicine, Rheumatology Unit, Stockholm, Sweden.
pubmed:publicationType
Journal Article