The serine proteinase hepsin is an activator of pro-matrix metalloproteinases: molecular mechanisms and implications for extracellular matrix turnover.

Increasing evidence implicates serine proteinases in the proteolytic cascades leading to the pathological destruction of extracellular matrices such as cartilage in osteoarthritis (OA). We have previously demonstrated that the type II transmembrane serine proteinase (TTSP) matriptase acts as a novel initiator of cartilage destruction via the induction and activation of matrix metalloproteinases (MMPs). Hepsin is another TTSP expressed in OA cartilage such that we hypothesized this proteinase may also contribute to matrix turnover.

Matriptase Induction of Metalloproteinase-Dependent Aggrecanolysis In Vitro and In Vivo: Promotion of Osteoarthritic Cartilage Damage by Multiple Mechanisms.

Objective: To assess the ability of matriptase, a type II transmembrane serine proteinase, to promote aggrecan loss from the cartilage of patients with osteoarthritis (OA) and to determine whether its inhibition can prevent aggrecan loss and cartilage damage in experimental OA.

Methods: Aggrecan release from human OA cartilage explants and human stem cell-derived cartilage discs was evaluated, and cartilage-conditioned media were used for Western blotting. Gene expression was analyzed by real-time polymerase chain reaction.

Matriptase is a novel initiator of cartilage matrix degradation in osteoarthritis.

Objective: Increasing evidence implicates serine proteinases in pathologic tissue turnover. The aim of this study was to assess the role of the transmembrane serine proteinase matriptase in cartilage destruction in osteoarthritis (OA).

Methods: Serine proteinase gene expression in femoral head cartilage obtained from either patients with hip OA or patients with fracture to the neck of the femur (NOF) was assessed using a low-density array.

Metalloproteases as potential therapeutic targets in arthritis treatment.

Dysregulated proteolysis of the extracellular matrix of articular cartilage represents a unifying hallmark of the arthritides, and has been a target for therapeutic intervention for some time, although clinical efficacy has been elusive. Members of the 'A disintegrin and metalloprotease with thrombospondin motifs' and matrix metalloprotease families are considered to be collectively responsible for cartilage catabolism, such that inhibition of these activities is theoretically a highly attractive strategy for preventing further proteolytic damage. This review outlines the biology of these metalloproteases and what we have learnt from inhibition studies and transgenics, and highlights the important questions that this information raises for the future development of therapeutics directed towards metalloproteases for arthritis treatment.

Metalloproteinase and inhibitor expression profiling of resorbing cartilage reveals pro-collagenase activation as a critical step for collagenolysis.

Excess proteolysis of the extracellular matrix (ECM) of articular cartilage is a key characteristic of arthritis. The main enzymes involved belong to the metalloproteinase family, specifically the matrix metalloproteinases (MMPs) and a group of proteinases with a disintegrin and metalloproteinase domain with thrombospondin motifs (ADAMTS). Chondrocytes are the only cell type embedded in the cartilage ECM, and cell-matrix interactions can influence gene expression and cell behaviour.

Fibroblast activation protein alpha is expressed by chondrocytes following a pro-inflammatory stimulus and is elevated in osteoarthritis.

Arthritis is characterised by the proteolytic degradation of articular cartilage leading to a loss of joint function. Articular cartilage is composed of an extracellular matrix of proteoglycans and collagens. We have previously shown that serine proteinases are involved in the activation cascades leading to cartilage collagen degradation.

Matrix metalloproteinase knockout studies and the potential use of matrix metalloproteinase inhibitors in the rheumatic diseases.

The matrix metalloproteinases (MMPs) comprise a family of enzymes that collectively can degrade all components of the extracellular matrix (ECM). MMPs play an important role in many physiological processes such as embryonic development and growth, tissue remodelling and repair. Overexpression and activation of MMPs contributes to many pathologies, including arthritis, cardiovascular disease, tumour progression and lung disease.