Effect of inhibition of matrix metalloproteinases on cartilage loss in vitro and in a guinea pig model of osteoarthritis

Abstract

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 shamoperated 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 aggrecanasedependent 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.Conclusion. 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.Osteoarthritis (OA) is a major joint disease in humans and various animals in which articular cartilage degenerates over a period of time and leads to denudation of the joint surface. This degeneration is mainly characterized by a progressive degradation of extracellular matrix (ECM) components, followed by chondrocyte death, tissue fibrillation, and erosion (1). Metalloproteinases of 2 families seem to play a major role in cartilage ECM breakdown. These are 1) aggrecanases, which, starting at an early stage of disease, specifically degrade ...

A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models

“…Evaluation of these compounds in selectivity assays against various MMPs (MMP-1, 2, 3, 7, 8, 9, 12, and 14) and other related zinc metalloproteinases including TACE and aggrecanase revealed Ͼ20,000 nM selectivity ( Table 1). In contrast, selectivity data on Ilomastat (Table 1) and other broad-spectrum inhibitors reported in the literature indicate that, although potent against MMP-13 activity, the broad-spectrum inhibitors lack selectivity (3,5,33,34). The only other MMP inhibitors with selectivity comparable with that of the MMP-13 inhibitors in the present study are the class of MMP-13 inhibitors recently reported in the literature (21).…”

“…MMPs have long been considered excellent targets for treatment of osteoarthritis (OA), and inhibition of their activity has proven to be efficacious in a variety of models of experimentally induced as well as spontaneously occurring disease (2)(3)(4)(5). However, the clinical utility of broad-spectrum MMP inhibitors developed for treatment of OA has been restricted by dose-and duration-dependent musculoskeletal side effects in humans (joint stiffness, inflammation, pain in the hands, arms, and shoulders termed "musculoskeletal syndrome" [MSS]).…”

Baicalein Inhibits MMPs Expression via a MAPK-Dependent Mechanism in Chondrocytes

“…MMPs is a family of enzymes that contribute to cartilage degradation through degrading extracellular matrix (EMC) while IL-1β is a cytokine that contributes to cartilage degradation by inducing the expression of MMPs and other proteases [3,4]. Previous studies demonstrated that the inhibition of IL-1β or MMP expression using pharmacologic inhibitors exerted beneficial effects on OA [5,6].…”

Potential directions for drug development for osteoarthritis

“…Several synthetic oral inhibitors of MMPs have been developed. They are effective in vitro and in animal models of OA [23,24]. However, trials in humans have been disappointing, either because of adverse side effects, such as musculoskeletal pain and tendonitis, or because the drugs lacked efficacy.…”