Inhibition of osteoclasts prevents cartilage loss and pain in a rat model of degenerative joint disease.

Abstract

OBJECTIVE:

To investigate the relationship between efficacy of a bisphosphonate, pain and extent of joint damage in the monosodium iodoacetate (MIA) model of painful degenerative joint disease.

METHODS:

Zoledronate treatment was initiated prior to and at various times following model induction, including late time points representing advanced disease. Radiographic and histological structural parameters were correlated with pain as measured by weight bearing.

RESULTS:

Intraarticular (IA) MIA resulted in a progressive loss of bone mineral density (BMD) and chondrocytes, thinning of cartilage, loss of proteoglycan, resorption of calcified cartilage and subchondral bone, as well as pain. This was completely prevented by pre-emptive chronic zoledronate treatment with joint sections being histologically indistinguishable from saline-injected controls. When initiation of treatment was delayed efficacy was reduced. In animals with advanced joint degeneration, treatment partially restored BMD and had a significant, but limited, effect on pain. We confirmed these radiographic and behavioral findings in the medial meniscal tear model. To understand the mechanism-of-action of zoledronate we investigated an early time point 4 days post-model induction when chondrocytes were histologically viable, with minor loss of proteoglycan and generalized synovitis. Osteoclast-mediated resorption of the calcified cartilage was observed and was prevented by two doses of zoledronate.

CONCLUSION:

Subchondral bone remodeling plays an important role in nociception and the pathobiology of the MIA model with osteoclasts being implicated in both bone and cartilage resorption. Inhibition of osteoclastic activity when initiated early leads to improved efficacy.

• Authors: B W Strassle, L Mark, L Leventhal, M J Piesla, X Jian Li, J D Kennedy, S S Glasson, G T Whiteside
• Journal: Osteoarthritis and cartilage (Osteoarthritis Cartilage) Vol. 18 Issue 10 Pg. 1319-28 (Oct 2010) ISSN: 1522-9653 [Electronic] England
• PMID: 20633675 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Bone Density Conservation Agents
• Diphosphonates
• Imidazoles
• Iodoacetates
• Zoledronic Acid

Topics

• Animals
• Arthritis, Experimental (complications, drug therapy, pathology, physiopathology)
• Bone Density (drug effects)
• Bone Density Conservation Agents (administration & dosage, therapeutic use)
• Cartilage, Articular (drug effects, pathology)
• Diphosphonates (administration & dosage, therapeutic use)
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical (methods)
• Imidazoles (administration & dosage, therapeutic use)
• Iodoacetates
• Male
• Osteoarthritis (complications, drug therapy, pathology, physiopathology)
• Osteoclasts (drug effects)
• Pain (etiology, prevention & control)
• Rats
• Rats, Sprague-Dawley
• Zoledronic Acid