Imbalance of local bone metabolism in inflammatory arthritis and its reversal upon tumor necrosis factor blockade: direct analysis of bone turnover in murine arthritis

Rheumatoid arthritis (RA) is one of the most typical examples of a chronic inflammatory process, which leads to profound changes of the skeleton [1]. In fact, RA and other forms of chronic arthritis are major precipitators of bone loss. Structural skeletal damage plays a major role in the outcome of RA patients since functional disability is a result of accumulating changes of the joint architecture [2]. Typically, juxta-articular bone is the skeletal site most exposed to the chronically inflamed RA synovial membrane, which directly invades bone and leads to formation of local erosions. These local bone erosions are characteristic for RA and are part of the diagnostic criteria of the disease [3].The underlying mechanisms leading to the excessive bone loss in RA are not fully understood, although some key interactions between inflammation and bone, such as the receptor activator of NF-κB ligand (RANKL), have been unraveled during recent years [4-6]. Since bone loss is always the result of a negative net balance of bone formation and resorption, mediators expressed within the synovial tissue are thought to induce a shift from bone formation to bone resorption. For instance, tumor necrosis factor (TNF) enhances osteoclast formation, and thus bone resorption, but it has also negative effects on bone formation since it interferes with differentiation and metabolic activity of osteoblasts [7-9].The pathological role of altered bone turnover in destructive arthritis is strongly supported by the detection of osteoclasts at sites of local bone erosion. These cells are localized at the interphase of inflammatory tissue and bone, and are found in all animal models of destructive arthritis as well as in human RA [10-13]. Moreover, osteoclast precursors form in the synovial inflammatory tissue, allowing a continuous replenishment of the osteoclast pool necessary to achieve progressive bone damage [5]. Kinetic studies in animal models have also shown that osteoclast formation in