Osteoarthritis: Pathobiology—targets and ways for therapeutic intervention☆

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Abstract

Osteoarthritis is first and foremost the ongoing destruction of the articular cartilages of joints. Therefore, the extracellular matrix and the cells of the articular cartilages are the primary targets of osteoarthritis therapy. This tries to inhibit enzymatic destruction of the extracellular cartilage matrix as well as the modification of the cellular phenotype of the chondrocytes: cell degeneration and cell death are alongside anabolic activation and stabilization of the cellular phenotype of major interest. However, apart from the cartilage and its cells, other tissues of the joints are also important for the symptoms of the disease, which basically all originate outside the articular cartilage. In addition, changes in the subchondral bone as well as the synovial capsule and membrane are important at least for the progression of the disease process.

All the named tissues offer different directions and ways for therapeutic intervention.

Section snippets

Introduction—the scenario of osteoarthritis

Osteoarthritis, the degeneration of the joints, is the most common disabling condition in the Western world. Clinically, degeneration affects mostly the large weight bearing joints of the legs (i.e. hips and knees), but can in principle affect any joint of the body including, notably, the finger joints. Osteoarthritis is not a single disease entity, but represents a disease group with rather different underlying pathophysiological mechanisms. In this respect, primary osteoarthritis has to be

Joint physiology—functioning of an organ system

Joints are highly specialized organs that allow repetitive pain-free and largely frictionless movements. These properties are provided by the articular cartilage and its extracellular matrix, which under physiological conditions is capable of sustaining high cyclic loading. Articular cartilage covers the joint surfaces and is mainly responsible for the unique biomechanical properties of the joints. Joints are, however, complex composites of different types of connective tissue including

The maintenance of the joint–the maintenance of the extracellular matrix

In normal human articular cartilage, aggrecan core and link proteins exist as a heterogeneous population [20], [21], [22] differing in size and composition as a result of differential post-translational glycosylation and proteolysis [23]. Normal proteolytic aggrecan turnover is highly regulated and is most probably implemented by the action of MMPs, particularly MMP-3 [24]. However, a second cleavage site, the ‘aggrecanase’ site, has also been described in the interglobular domain and

Osteoarthritis–disease of an organ system–tissues to be targeted

Primary osteoarthritis of the large weight-bearing joints is generally the result of an imbalance between applied mechanical stress and the physico-chemical ability of the articular cartilage to resist this stress. In the end, osteoarthritis results from the destruction and failure of the extracellular matrix, the functional element of articular cartilage. However, osteoarthritis is a disease of the joint as an organ system, not only of the articular cartilage. This includes all connective

Cartilage repair: option for therapeutical intervention

At the margins of joints, in particular in osteoarthritic joint disease, frequently (osteo)cartilaginous outgrowths appear ((chondro-)osteophytes). They are best considered as a process of secondary chondroneogenesis in the adult [101]. Osteophytes derive from mesenchymal precursor cells within periosteal or synovial tissue and often merge with or overgrow the original articular cartilage [136], [137]. Thus, in this process, mesenchymal precursor cells differentiate into chondrocytes. A

Perspectives

Clearly, genomics, defined either as specific gene defects or as a rather undefined genetic background, plays an important role for the initiation and the progression of the osteoarthritic disease process [166]. Responsible genes have, however, been difficult to identify and might be different for different joints (for review, see Loughlin [167]). Still this will be one important focus of future research and will certainly provide new targets for therapeutic intervention. Also, better

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    ☆

    This review is part of the Advanced Drug Delivery Reviews theme issue on “Drug Delivery in Degenerative Joint Disease”, Vol. 58/2, 2006.

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