Degradation of small leucine-rich repeat proteoglycans by matrix metalloprotease-13: identification of a new biglycan cleavage site

Osteoarthritis (OA) is the most common rheumatologic disease, with high incidence and morbidity. Even though the early pathophysiological process remains to be elucidated, one of the first alterations in OA cartilage is a decrease in proteoglycan content [1]. Proteoglycans form a large group that can be classified into five families according to the structural properties of their core protein [2]. One group, termed the small leucine-rich proteoglycans (SLRPs), possesses a central domain of characteristic repeats that participate in protein-protein interactions [3]. The SLRPs can be divided into four classes based on gene organization and amino acid sequence homologies [1]: class I includes decorin, biglycan and asporin; class II includes fibromodulin, lumican, keratocan, PRELP (proline arginine-rich end leucine-rich repeat protein) and osteoadherin; class III includes epiphycan, mimecan and opticin; and class IV includes chondroadherin and the recently identified nyctalopin [4].Although an understanding of the functions of SLRPs is only now emerging, most of the members bind specifically to other extracellular matrix constituents and contribute to the structural framework of connective tissues [3]. Moreover, some were shown to interact with various collagen types, including collagen type II, and to influence collagen fibril formation and interaction. These include decorin [5], fibromodulin [6], asporin [7], lumican [8], PRELP [9] and chondroadherin [10]. Moreover, fibromodulin, asporin, biglycan, decorin and lumican were also suggested to play a role in the OA cartilage process [11-13].Decorin was the first in this series of molecules to be structurally defined. It contains one glycosaminoglycan chain, often dermatan sulfate, which can adopt complex secondary structures and form specific interactions with matrix molecules [3]. The decorin level in cartilage is by far the most abundant of the SLRPs, and in humans its level increases with increasing age [14]. Its prop