Our overall goal is to shed light upon the metabolism of three matrix molecules playing important functional roles in articular cartilage. The first two, hyaluronan (HA) and aggrecan, interact to form aggregates which give the tissue its unique properties of resilience (1). The third, cartilage oligomeric matrix protein (COMP), is an abundant non-collagenous protein; however, its function and metabolism in the matrix are poorly understood (2). Recent studies have revealed that high serum levels of COMP (3) and/or HA (4) at entry were characteristic of patients with osteoarthritis (OA) who exhibited rapid joint destruction. We hypothesize that interleukin-1 (IL-1), a signaling molecule found in OA synovium and cartilage during inflammatory episodes (5) (or other mediators with similar modes of action upon chondrocyte metabolism), contributes to the progressive joint destruction which these serum marker prognosticate. New support for this hypothesis come from our recent finding that IL-1 at 1 ng/ml uncouples the coordinated synthesis of HA (up-regulation) and aggrecan (down-regulation) by bovine adult articular chondrocytes, causing rapid loss of matrix homeostasis (6).
The first aim of this proposal is to define the mechanisms regulating the synthesis and turnover of COMP, HA and aggrecan in articular cartilage matrix maintaining a steady state metabolism in culture.
The second aim i s to then fully characterize the dose-dependent effects of exposure of the chondrocytes to IL-1 upon anabolic and catabolic processes responsible for normally maintaining these molecules at a constant level in the cartilage matrix. The studies will be performed using both explants and chondrocytes isolated from articular cartilage of young adult bovine animals and adult human donors without a history of joint disease. The chondrocytes will be cultured in alginate gel to distinguish between metabolic events i in the metabolically active (cell-associated) and less active (further removed) matrix compartments. Certain of these studies will attempt to define differences in the metabolism of cells from the most superficial and a deeper zone of articular cartilage. These studies will shed light on the biochemical and metabolic bases of the prognostic values of serum levels of COMP, HA and aggrecan-related epitopes in OA and other joint diseases.
Showing the most recent 10 out of 305 publications
