Cartilage Cell and Matrix Response to Joint Loading

Hospital For Special Surgery, New York NY

Investigators

Linked publications & trials

Abstract

[unreadable] DESCRIPTION (provided by applicant): Little is known about how mechanical loads can initiate the degenerative process in articular cartilage leading to osteoarthritis (OA). Our long-term goal has been to characterize the sequence of physical and cellular events that initiate the degenerative process. To study the degenerative process within a controlled laboratory environment, we used our mechanic explant test system (METS) to model OA by applying an excessive mechanical load (EML) to bovine articular cartilage. Our test system was able to initiate a pathological cascade of events similar to that observed in early stage human and animal OA, including increased enzymes, collagen degradation, proteoglycan loss, and cell death, all localized at the articular surface within the superficial zone (SZ). We have shown that the mechanically-induced damage in the SZ is most-likely cell mediated through the release of three specific metalloproteinases for collagen and aggrecan cleavage, MMPs-1 and 13 (collagenase-1 and 3) and MMP-3 (Stromelysin-1), respectively. However, these results are in contrast to inflammatory-cytokine induced models of OA (IL-1 stimulated) in which aggrecanase-1 and 2 (ADAM-TS4 and 5) were found to initiate the degradation process by aggrecan cleavage. This data leads us to hypothesize that there are two different mechanisms (pathways) of matrix degradation for EML and inflammatory-induced matrix damage. More important, however, is that preliminary results combining both mechanical load and IL-1 stimulation indicate that mechanical loads may inhibit the deleterious effects of IL-1 mediated cell-catabolism by the down-regulation of aggrecanase matrix degradation. We thus further hypothesize that mechanical loads can modulate the degradation process through matrix deformation, that is, by changing the matrix susceptibility to degradation by aggrecanase-1 and 2 and MMPs-1, 3 and 13. The goal of this proposal is to characterize the sequence of degradative events involved in the initiation of matrix damage by EML, to delineate the mechanisms of damage to aggrecan and collagen at the molecular level, to correlate these events and damage to the functional properties (biochemical and biomechanical) of the tissue, and to compare these parameters to those obtained for IL-1 induced damage. If, as we believe, two distinct initiation mechanisms exist, then this would significantly alter how we study each disease process and how we will need to treat them to prevent the progression of the disease. [unreadable] [unreadable]