Fibronectin-fragment-induced cartilage chondrolysis is associated with release of catabolic cytokines

Abstract

Fibronectin fragments have both catabolic and anabolic activities toward articular cartilage explants in vitro. Whereas a 1 nM concentration of an N-terminal 29 kDa fibronectin fragment (Fn-f) increases the proteoglycan (PG) content of cartilage without induction of matrix metalloproteinases (MMPs), 0.1Ő1 ƁM Fn-f temporarily suppresses PG synthesis and enhances MMP release. The higher concentrations cause an initially rapid PG depletion during the first week of culture, followed by much slower PG loss and gradually increasing rates of PG synthesis. To test for the involvement of mediators, human articular cartilage was cultured with Fn-f, and conditioned media were assayed for selected cytokines and factors. With 1 nM Fn-f, the release of the anabolic factors, insulin growth factor-I and transforming growth factor β1, from cultured cartilage was enhanced by 50Ő100% during the entire 28-day culture period and this was associated with both supernormal rates of PG synthesis and PG content. However, the higher concentrations of Fn-f additionally enhanced release, by at least 10-fold, of the cytokines, tumour necrosis factor α, interleukin-1α, interleukin-1β and interleukin-6 while causing depletion of cartilage PG. Release of tumour necrosis factor α, interleukin 1β and interleukin 1α peaked at days 2, 3 and 9 during or slightly after the period of maximal PG depletion and decreased to control levels by days 7, 7 and 21 respectively, whereas release of interleukin 6 was enhanced throughout the culture period. Neutralizing antibodies to the catabolic cytokines reduced Fn-f-mediated MMP-3 release and suppression of PG synthesis. The temporal aspects of this interplay between catabolic and anabolic factors are consistent with the kinetics of Fn-f-mediated cartilage damage and attempted repair and may be relevant to cartilage damage and repair in vivo.

Cathepsins B, K, and L Are Regulated by a Defined Collagen Type II Peptide via Activation of Classical Protein Kinase C and p38 MAP Kinase in Articular Chondrocytes

“…Chondrocytes may release enzymes that mediate the normal turnover of extracellular matrix but may also lead to its uncontrolled pathologic degradation. Recently, it has been shown that fibronectin fragments induce proteoglycan and collagen type II degradation and that this pathway may substantially contribute to the maintenance of arthritic processes and finally to chondrocytic chondrolysis (43)(44)(45). Fibronectin fragments induce the release of catabolic cytokines in cartilage explants (46).…”

Inhibitory Effects of Insulin-like Growth Factor-1 and Osteogenic Protein-1 on Fibronectin Fragment- and Interleukin-1β-stimulated Matrix Metalloproteinase-13 Expression in Human Chondrocytes

“…Several studies have shown that Fn-f increase MMP expression via an IL-1 autocrine loop (36,37). On the other hand, stimulated expression of MMPs mediated by an IL-1-independent mechanism has been reported (38).…”

A fibronectin fragment induces type II collagen degradation by collagenase through an interleukin-1?mediated pathway

“…Elevated levels of FN are found in OA cartilage (36)(37)(38) and in OA SF (38,39). The central cell-, aminoterminal heparin-, and amino-terminal gelatin-binding fragments of FN have been shown to stimulate PG breakdown (40) and release of catabolic cytokines (41,42) in cultured articular cartilage explants. Rabbit synovial fibroblasts, plated on the central RGDcontaining cell-binding region of FN, express elevated levels of collagenase (43).…”