Osteoarthritis (OA) is a non-inflammatory disease, even though there may be inflammatory episodes. Thus, the typical inflammatory mediators may not continuously induce chondrocytic chondrolysis (cartilage breakdown mediated by the endogenous chondrocytes). During the non-inflammatory periods, there may be other mediators of damage. We propose that degradation components of the extracellular matrix (ECM) play active roles in driving matrix destruction. We have documented that fibronectin (Fn) fragments (Fn-f) enhance catabolic mediator levels and induce matrix metalloproteinases (MMPs), resulting in cartilage degradation. Further, our preliminary data show that collagen type II (col II) fragments (col- f) and hyaluronan (HA) fragments (HA-f) also induce cartilage damage. Thus, while the components of the normal ECM influence the synthesis, assembly and degradation of macromolecules by chondrocytes, the fragmented components of the damaged matrix alter this influence or feedback- regulation and contribute to progression of damage. A key point is that the parent molecules may also be elevated in various states of OA, and would contribute to enhanced levels of ECM fragments. It is also likely that the ECM fragments alter synthesis of matrix molecules under and certain conditions, these may enhance reparative processes, as shown for the Fn-f. Thus, the ECM fragments may complete the linkage between damage and subsequent attempted repair in OA. Characterization of the effects of fragment should suggest means of intervention to reduce metabolic damage and thereby facilitate repair in OA. We propose (1) to investigate whether enhancement of Fn levels by anabolic factors added to cartilage ultimately contributes to cartilage damage through generation of Fn-f. We will also test whether injection of Fn-f into rabbit knee joints, in an established model, also leads to enhanced levels of Fn, which ultimately would contribute to cartilage damage. We propose (2) to investigate the activities of collagen type II fragments (col-f) and HA fragments (HA-f) in mediating damage to cartilage explants in bovine and human tissue and regulating chondrocyte metabolism, based on our preliminary observations that these fragments do cause loss of PG and induction of MMPs in cartilage explants. Their effects on cartilage damage when injected into rabbit knee joints will also be assessed. We propose (3) to investigate the role of the Fn-binding integrin, col II binding anx V and HA binding CD44 in the regulation of cartilage homeostasis by the respective fragments, based on preliminary data that suggest involvement of these receptors.
Showing the most recent 10 out of 305 publications
