Inhibition of cathepsin K reduces bone erosion, cartilage degradation and inflammation evoked by collagen-induced arthritis in mice.
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.
Karolinska Institutet, Department of Medicine, Rheumatology Unit, Stockholm, Sweden.
Lena
L
Svelander
Helena
H
Erlandsson-Harris
Leif
L
Astner
Urszula
U
Grabowska
Lars
L
Klareskog
Erik
E
Lindstrom
Ellen
E
Hewitt
D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000517:prevention & control; D001549:Benzamides / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D001862:Bone Resorption / Q000188:drug therapy / Q000209:etiology; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002356:Cartilage / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D003094:Collagen / Q000009:adverse effects*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011480:Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
D001549:Benzamides; D015415:Biomarkers; C507712:CRA 013783; D011480:Protease Inhibitors; D013844:Thiazoles; D003094:Collagen; D002403:Cathepsins; C028217:cathepsin S; C534130:CTSK protein, human; D056657:Cathepsin K; C534132:Ctsk protein, mouse