Selective and non-selective metalloproteinase inhibitors reduce IL-1-induced cartilage degradation and loss of mechanical properties

Abstract

Articular cartilage undergoes matrix degradation and loss of mechanical properties when stimulated with proinflammatory cytokines such as interleukin-1 (IL-1). Aggrecanases and matrix metalloproteinases (MMPs) are thought to be principal downstream effectors of cytokine-induced matrix catabolism, and aggrecanase-or MMP-selective inhibitors reduce or block matrix destruction in several model systems. The objective of this study was to use metalloproteinase inhibitors to perturb IL-1-induced matrix catabolism in bovine cartilage explants and examine their effects on changes in tissue compression and shear properties. Explanted tissue was stimulated with IL-1 for up to 24 days in the absence or presence of inhibitors which were aggrecanase-selective, MMP-selective, or non-selective. Analysis of conditioned media and explant digests revealed that aggrecanase-mediated aggrecanolysis was delayed to varying extents with all inhibitor treatments, but that aggrecan release persisted. Collagen degradation was abrogated by MMP-and non-selective inhibitors and reduced by the aggrecanase inhibitor. The inhibitors delayed but did not reduce loss of the equilibrium compression modulus, whereas the loss of dynamic compression and shear moduli was delayed and reduced. The data suggest that non-metalloproteinase mechanisms participate in IL-1-induced matrix degradation and loss of tissue material properties.

Alteration of articular cartilage frictional properties by transforming growth factor β, interleukin‐1β, and oncostatin M

“…The observed rates of proteoglycan loss from IL-1␤-and OSM-treated explants ( Figure 5A) were consistent with the findings of previous studies (34,41,42,52), establishing the validity of our experimental setup as a catabolic model. IL-1␤ decreased E Y (Figure 5B), consistent with changes in aggregate modulus demonstrated in other studies (34,52). In contrast, this is the first study to demonstrate the functional mechanical consequences of OSM-induced matrix catabolism.…”

“…IL-1␤ is known to induce collagen degradation in cartilage explants that is manifest in functional changes in shear modulus (34) and tissue swelling (52). Further studies should be conducted to examine the role of these changes in tissue structure and properties induced by IL-1␤ (e.g., surface roughness and collagen loss and/or disruption) in friction and lubrication of cartilage.…”

“…IL-1␤ is a potent mediator of proteoglycan loss and is associated with the disruption of collagen structure (34), while TGF␤ up-regulates proteoglycan synthesis (35,36). The role of proteoglycan content on the frictional properties of articular cartilage remains unclear, with some studies demonstrating a dependence (37) and others independence (38) of the equilibrium friction coefficient on proteoglycan content.…”

Inhibition of Matrix Metalloproteinases Enhances In Vitro Repair of the Meniscus

“…However, it is possible the aggrecanases play a larger role in meniscal healing than is observed in IL-1-stimulated explant culture. In addition to MMPs and aggrecanases, other degradative enzymes also may be involved in preventing meniscal repair in an inflammatory microenvironment (eg, cathepsin B, cathepsin K, hyaluronidase, and/or others [31,56]). …”

High levels of glucosamine–chondroitin sulfate can alter the cyclic preload and acute overload responses of chondral explants

“…Also, as suggested in studies by others that examined effects of selective and nonselective metalloproteinase inhibitors on interleukin-1-induced cartilage degradation, the effects of media supplementation on altering the cartilage material properties may only be delayed in time. 24 Future studies should determine if the same effects are seen with an extended duration of cyclic loading of the supplemented explants.…”