Effect of inhibition of matrix metalloproteinases on cartilage loss in vitro and in a guinea pig model of osteoarthritis.
OBJECTIVE
To study the effects of a matrix metalloproteinase (MMP) inhibitor (S-34219) on osteoarthritis (OA) cartilage cultures and in the meniscectomized guinea pig model of OA.


METHODS
The inhibitory activity of S-34219 on MMPs and aggrecanase was studied by fluorimetry and immunoassay, respectively. The effects of S-34219 on proteoglycan and collagen degradation were studied in cultures of rabbit and human cartilage. Medial meniscectomy was performed on 29 Hartley male guinea pigs, and these animals were randomly allocated to 1 of 3 groups: a control meniscectomized group (MNXc) receiving the vehicle, or a meniscectomized group receiving either 10 mg/kg or 20 mg/kg S-34219, administered twice per day by oral gavage for 12 weeks from day 1 after surgery. An additional group comprised sham-operated animals. Tibial cartilage from the operated left knee was processed for histologic assessment of OA lesions.


RESULTS
The 50% inhibitory concentration (IC(50)) of S-34219 on MMPs 1, 2, 3, 8, 9, and 13 was 55, 0.1, 0.5, 0.1, 0.03, and 0.2 nM, respectively; the IC(50) on aggrecanase 1 was 190 nM. In cultured rabbit cartilage, 100 nM S-34219 strongly inhibited MMP-dependent degradation of collagen and proteoglycans. A concentration 100 times higher was needed to inhibit aggrecanase-dependent degradation. In cultures of human OA cartilage, 100 nM S-34219 inhibited spontaneous type II collagen degradation by 66% and proteoglycan degradation by only 22%. For in vivo studies, treated groups were compared with the MNXc group and the results, expressed as the percentage variation versus MNXc, were as follows: in the 10 and 20 mg/kg groups, a significant decrease (P < 0.05) in global histologic score (-12% and -14%, respectively) was observed, and this was associated with a significant increase (P < 0.05) in cartilage thickness (+19% and +18%, respectively). Neither dose level changed the proteoglycan content.


CONCLUSIONS
In both treated animal groups, S-34219 significantly prevented the loss of cartilage thickness, probably by inhibiting collagen breakdown that normally leads to the erosion of fibrillated superficial areas. The absence of a protective effect on glycosaminoglycan loss, both in vitro and in vivo, suggests that aggrecanases may have an important role in cartilage loss. This study reinforces the relevance of these models for testing chondroprotective drugs, and the potential role of dual inhibitors of collagenase and aggrecanase as disease-modifying drugs in the management of OA.
Sabatini
Massimo
M
Division of Rheumatology, Institut de Recherches Servier, 11 rue des Moulineaux, 92150 Suresnes, France.
Lesur
Christophe
C
Thomas
Marie
M
Chomel
Agnès
A
Anract
Philippe
P
de Nanteuil
Guillaume
G
Pastoureau
Philippe
P
D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004838:Epiphyses / Q000473:pathology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007719:Knee Joint / Q000201:enzymology / Q000473:pathology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D010003:Osteoarthritis / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011509:Proteoglycans / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D013450:Sulfones / Q000494:pharmacology*; D013977:Tibia / Q000473:pathology
C496218:6-(4-(4-imidazol-1-ylphenoxy)benzenesulfonyl)-4,5,6,7-tetrahydrofuro(2,3-c)pyridine-5-carboxylic acid; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011509:Proteoglycans; D011725:Pyridines; D013450:Sulfones