Evaluation of a magnetic resonance biomarker of osteoarthritis disease progression: doxycycline slows tibial cartilage loss in the Dunkin Hartley guinea pig
- 18 March 2009
- journal article
- Published by Wiley in International Journal of Experimental Pathology
- Vol. 90 (2), 174-181
- https://doi.org/10.1111/j.1365-2613.2008.00634.x
Abstract
The objective was to assess the effect of doxycycline treatment on a magnetic resonance imaging (MRI) biomarker of cartilage volume loss, and on matrix metalloproteinase (MMP) activity in a guinea pig osteoarthritis model. Guinea pigs (9 months old) were dosed with vehicle or doxycycline, 0.6, 3.0 mg/kg/day for 66 days. Fat-suppressed 3D gradient-echo MRI of the left knee was acquired pre- and post dosing. Change in medial tibial plateau (MTP) cartilage volume (MT.VC) was determined using image analysis. At termination, MTP cartilage was removed from knees and proteolytic MMP activity determined using a fluorescent peptide substrate assay. Vehicle-treated animals lost 20.5% (95% CI mean 25.6-15.1) MT.VC. The doxycycline (0.6 mg/kg/day) group lost 8.6% (P < 0.05, 95% CI 20.6 to -5.3) whilst the 3.0 mg/kg/day group lost 10.0% (P < 0.05, 95% CI 13.9-6.0%). Endogenous levels of active MMPs were below limits of detection in all samples. However, doxycycline treatment ablated amino phenyl mercuric acid activated MMP-13 and MMP-8 levels, reduced MMP-9 levels by 65% and MMP-1 levels by 24%. Doxycycline treatment resulted in partial protection from MT.VC loss and was associated with complete reduction in MMP-13 and MMP-8, and partial reduction in MMP-9 activity. These data imply a role of MMPs in cartilage degeneration but incomplete protection suggests that additional doxycycline insensitive mechanisms are important in this model. The protective effect of doxycycline correlates with the clinical finding of lessened joint space narrowing, strengthens the utility of this animal model in identifying disease-modifying osteoarthritic drugs and supports the use of MRI biomarkers of cartilage loss.Keywords
This publication has 31 references indexed in Scilit:
- P64 CHARACTERISATION OF TEMPORAL CHANGES OF AGGRECANASE-DEPENDANT PROTEOGLYCAN LOSS IN THE GUINEA PIG MODEL OF SPONTANEOUS OAOsteoarthritis and Cartilage, 2006
- Magnetic resonance imaging (MRI) of articular cartilage in knee osteoarthritis (OA): morphological assessmentOsteoarthritis and Cartilage, 2006
- Change in joint space width: Hyaline articular cartilage loss or alteration in meniscus?Arthritis & Rheumatism, 2006
- Fundamental subchondral bone changes in spontaneous knee osteoarthritisThe International Journal of Biochemistry & Cell Biology, 2005
- Enhanced cleavage of type II collagen by collagenases in osteoarthritic articular cartilage.JCI Insight, 1997
- Cloning, expression, and type II collagenolytic activity of matrix metalloproteinase-13 from human osteoarthritic cartilage.JCI Insight, 1996
- Treatment of Destructive Arthritic Disorders with MMP InhibitorsAnnals of the New York Academy of Sciences, 1994
- Prediction of the progression of joint space narrowing in osteoarthritis of the knee by bone scintigraphy.Annals Of The Rheumatic Diseases, 1993
- Effects of Body Weight Restriction on the Development and Progression of Spontaneous Osteoarthritis in Guinea PigsArthritis & Rheumatism, 1991
- Spontaneous cartilage degeneration in guinea pigsArthritis & Rheumatism, 1988