Proinflammatory mediators and osteoarthritis

Abstract

ALTHOUGH the etiology of osteoarthritis (OA) remains elusive, it is currently believed that the integrity of articular tissue is maintained through a balance in cytokine-driven anabolic and catabolic processes. OA is characterized by a degeneration of articular cartilage. Breakdown of the cartilage matrix leads to the development of fibrillation, fissures, the appearance of gross ulcerations, and full thickness loss of the joint surface. Moreover, at the clinical stage of the disease, changes caused by OA involve not only the cartilage, but also the synovial membrane where an inflammatory reaction is often seen. The occurrence of synovial inflammation in OA appears to be of fundamental importance mainly due to the secretion of mediators such as the cytokines [1]. Although the spectrum of factors responsible for the altered function of the cells in OA has not been fully defined, evidence suggests that the production of irregular cytokines and alterations in their amounts or operative mechanisms contribute to the abnormalities present. Among the proinflammatory cytokines, interleukin (IL)-1â and tumor necrosis factor (TNF)-a appear most involved in the catabolic process of OA [1]. The net e#ect of these proinflammatory cytokines depends not only on absolute levels, but on a complex interplay among ambient cytokines. Other inflammatory cytokines have been shown to be expressed in synovial membrane or fluid of OA patients (Fig. 1), these being the IL-6, leukemia inhibitory factor (LIF), IL-17 and IL-8. All are upregulated by the proinflammatory cytokines IL-1â and TNF-a, and also have the ability to increase the synthesis of the two latter. IL-1â is primarily synthesized as a 31 kD precursor (pro-IL-1â) and must be proteolitically processed to be active. In mammals only one protease, which belongs to the cysteine-dependent protease family and is named IL-1â converting enzyme (ICE or Caspase-1), can specifically generate the