Osteoarthritis (OA), the syndrome of joint pain and dysfunction caused by cartilage degeneration, affects more people than any other joint disease. It is characterized by degradation and loss of articular cartilage, subchondral bone remodeling, and, at the clinical stage of the disease, in–ammation of the synovial membrane. The main structural macromolecules in the cartilage matrix are type II collagen and aggrecan. In healthy tissue, there is a balance between anabolic and catabolic processes that allows matrix turnover, whereas in OA this balance shifts toward catabolism, leading to cartilage destruction. Currently, there are many treatments available for OA. Conservative measures begin with lifestyle modi—cations, such as weight loss and decreased activity. Current medications for OA, including nonsteroidal anti-in–ammatory drugs (NSAIDs) [1] or steroids [2], provide only symptomatic improvements. In particular, NSAID intake might have a deleterious structural effect in cases of OA, and ex vivo and in vivo studies have shown that some NSAIDs inhibit the synthesis of cartilage proteoglycans [3, 4], leading to decreased use in clinical practice. A relatively new treatment, hyaluronan injection, improves joint lubrication and can decrease pain [5]. The major disadvantage

Introduction .................................................................................................................................... 433 The Novel Protective Mechanisms of DHEA: Regulating the Anabolic/Catabolic

Balance of Articular Cartilage .................................................................................. 434 Regulating the Balance between MMPs and the Tissue Inhibitor of

Metalloproteinase-1: A De—nite Protective Mechanism of DHEA for Osteoarthritic Cartilage ............................................................................................. 434

Adjusting Cysteine Proteinases/Cystatin C Enzyme Expression: A Novel Mechanism of DHEA on Cartilage in Different Stages of OA .................................................... 435

Downregulating the Expression of the Urokinase Plasminogen Activator/Plasminogen Activator Inhibitor-1 Enzyme System: A Newly Discovered Mechanism of DHEA on Osteoarthritic Cartilage ............................................................................ 436

Modulating the Balance between Aggrecanases and the TIMP-3: A Speculated Mechanism of DHEA by which this Agent Exerts Its Protective Role in OA .......... 436

Perspectives .................................................................................................................................... 438 References ...................................................................................................................................... 438

of all current treatments is that they mainly target the symptoms of OA but do not address the fundamental mechanisms by which articular cartilage damage develops. Consequently, a novel treatment capable of protecting or regenerating cartilage extracellular matrix (ECM) is desirable.