MMP-8 (neutrophil collagenase) mRNA and aggrecanase cleavage products are present in normal and osteoarthritic human articular cartilage

Abstract

Osteoarthrosis is characterized by a progressive destruction of articular cartilage resulting from an imbalance of synthesis and degradation of aggrecan and collagen, the major matrix components. The process is governed by inflammatory episodes, thus the disease is called Osteoarthritis (OA). Aggrecan is a large proteoglycan (PG) which is responsible for the biomechanical function of the cartilage to withstand compressive loading. Aggrecan consists of a core protein to which chains of chondroitin and keratan sulfate are attached (Hascall 1988; Heinegård 1992). Cleavage of the core protein between the two globular domains at the animo terminal end results in loss of aggrecan from the cartilage and impaired function. A number of potential cleavage sites have been identified within the interglobular domain for different proteases including members of the family of matrix metalloproteinases (MMPs), lysosomal enzymes, plasmin, elastase and urokinase (Fosang et al. 1991; 1992; 1993). The predominant proteolytic product was identified by amino acid sequencing of the aggrecan core peptides which had been released into synovial fluid from human arthritic cartilage and culture media of bovine cartilage or Swarm rat chondrosarcoma stimulated by interleukin 1 or retinoic acid (Sandy et al. 1991; Ilic et al. 1992; Sandy et al. 1992; Loulakis et al. 1992; Lohmander et al. 1993; Lark et al. 1995). The protease responsible for the cleavage product was called “aggrecanase” and a search began to identify the enzyme. Recently, a MMP synthesized by neutrophils (MMP-8; neutrophil collagenase) was shown to be capable of generating the aggrecanase cleavage product in vitro (Fosang et al. 1994a; b). It is, however, still not known whether chondrocytes express MMP-8 (Hardingham et al. 1994); this protease was thought to be a unique gene product of neutrophils (Mainardi et al. 1991). In preliminary reports we described briefly that mMMP-8 is detectable by in situ hybridizstion in normal and osteoarthritic cartilages (Chubinskaya et al. 1995; Huch et al. 1995).