Inhibition of cathepsin K reduces cartilage degeneration in the anterior cruciate ligament transection rabbit and murine models of osteoarthritis.

Abstract

OBJECTIVE:

To investigate the disease modifying effects of cathepsin K (CatK) inhibitor L-006235 compared to alendronate (ALN) in two preclinical models of osteoarthritis (OA).

METHODS:

Skeletally mature rabbits underwent sham or anterior cruciate ligament transection (ACLT)-surgery and were treated with L-006235 (L-235, 10 mg/kg or 50 mg/kg, p.o., daily) or ALN (0.6 mg/kg, s.c., weekly) for 8-weeks. ACLT joint instability was also induced in CatK(-/-) versus wild type (wt) mice and treated for 16-weeks. Changes in cartilage degeneration, subchondral bone volume and osteophyte area were determined by histology and μ-CT. Collagen type I helical peptide (HP-I), a bone resorption marker and collagen type II C-telopeptide (CTX-II), a cartilage degradation marker were measured.

RESULTS:

L-235 (50 mg/kg) and ALN treatment resulted in significant chondroprotective effects, reducing CTX-II by 60% and the histological Mankin score for cartilage damage by 46% in the ACLT-rabbits. Both doses of L-235 were more potent than ALN in protecting against focal subchondral bone loss, and reducing HP-I by 70% compared to vehicle. L-235 (50 mg/kg) and ALN significantly reduced osteophyte formation in histomorphometric analysis by 55%. The Mankin score in ACLT-CatK(-/-) mice was ~2.5-fold lower than the ACLT-wt mice and was not different from sham-CatK(-/-). Osteophyte development was not different among the groups.

CONCLUSION:

Inhibition of CatK provides significant benefits in ACLT-model of OA, including: 1) protection of subchondral bone integrity, 2) protection against cartilage degradation and 3) reduced osteophytosis. Preclinical evidence supports the role of CatK as a potential therapeutic target for the treatment of OA.

• Authors: Tadashi Hayami, Ya Zhuo, Gregg A Wesolowski, Maureen Pickarski, Le T Duong
• Journal: Bone (Bone) Vol. 50 Issue 6 Pg. 1250-9 (Jun 2012) ISSN: 1873-2763 [Electronic] United States
• PMID: 22484689 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Benzamides
• Biomarkers
• Bone Density Conservation Agents
• CRA 013783
• Collagen Type I
• Cysteine Proteinase Inhibitors
• Peptide Fragments
• Peptides
• Thiazoles
• collagen type I trimeric cross-linked peptide
• Cathepsin K
• Ctsk protein, mouse
• Alendronate

Topics

• Alendronate (pharmacology)
• Animals
• Anterior Cruciate Ligament Injuries
• Benzamides (pharmacology)
• Biomarkers (metabolism)
• Bone Density Conservation Agents (pharmacology)
• Cartilage, Articular (pathology)
• Cathepsin K (antagonists & inhibitors, deficiency, genetics)
• Collagen Type I (metabolism)
• Cysteine Proteinase Inhibitors (pharmacology)
• Disease Models, Animal
• Disease Progression
• Female
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Osteoarthritis (enzymology, etiology, pathology, prevention & control)
• Peptide Fragments (metabolism)
• Peptides (metabolism)
• Rabbits
• Thiazoles (pharmacology)