Editorial [ Hot Topic: Current Drug Targets in Degenerative Joint Disease (Guest Editors: T. Aigner and E. Bartnik) ]

The more the baby-boomer generation ages, the more patients will be suffering from chronic, degenerative diseases, like osteoarthritis. This means they will experience pain, swelling, weakness and loss of functional ability in their diseased joints. These symptoms will progress to significantly impact the quality of life and the productivity of the affected people. In the US Centers for Disease Control report from 2002 “Prevalence of self-reported Arthritis of chronic joint symptoms among adults ” United States, 2001” the prevalance of arthritis/chronic joint symptoms were given as 33%, representing 69.9 million adults. This translates directly into a significant economic burden, which comprises both the direct costs (diagnosis, hospitalization, therapies) and the indirect costs including premature mortality, chronic and short-term disability and not to forget losses of productivity. Not surprisingly, indirect costs far exceed direct costs. Despite tremendous efforts to understand pathomechanisms of osteoarthritic joint changes both at the level of basic and at the level of applied research, the major unmet medical need for osteoarthritis remain disease-modifying agents and better diagnostic tools. With the COX-2 inhibitors we thought to have alternatives to NSAIDs with their gastrointestinal side effects to treat at least symptoms of osteoarthritis, but the withdrawal of rofecoxib (Vioxx; Merck) in September 2004 and the subsequent discussion on a class effect of coxibs in respect to cardiovascular risks, depredated us of our illusions. But did not biology advance tremendously in recent years with all its genomics, proteomics, metabolomics and other ‘omics’ to show hundreds of new molecules to explain the academic researchers the intricacies of disease pathways and at the same time to quench the thirst of the industry researcher for novel drug targets? Reading through the collected reviews, a tremendous amount of knowledge on individual targets has been gained. But quite notably, an other notion emanates from most of the reviews: Understanding individual targets does not seem to be sufficient to develop effective therapeutic strategies. Roach et al. set the stage by describing OA as a disease of an organ system, implying that a true understanding of the disease must eventually be based on ‘molecular portraits’ of the affected tissues including articular cartilage, bone, synovium, capsule, ligaments and muscles. Burrage and Brinckerhoff summarise our understanding of apparently the most obvious drug targets for OA, the proteases that are directly responsible for the degradation of the cartilage matrix components. Although some very attractive targets (MMP-13, ADAMTS aggrecanases and TACE) are known, they speculate, that we need to follow the concept of “molecular polypharmacy” i.e. to target several proteases at the same time to achieve clinical effects. Salminen-Mankonen et al. report on Cystein cathepsins, most notably on Cathepsin K, whose role as a protease responsible for degradative events in bone and in cartilage earns more attention than in the past, although here the development of tissue specific inhibitors poses problems. Turning to the level of communication between cells, Bloom et al. point towards cytokines with IL-1 inhibition shown to ameliorate OA-like pathology and TGFb providing an approach to promote cartilage integrity and repair, but also in the context of a combination therapy. Our hopes to find therapeutic approaches at the level of regulation of the MAPK and NFkB signaling pathways are dampened by Saklatvala with the arguments that it is not clear which pathway would have to be blocked for most effective MMP suppression and what effects it may have on normal cartilage turnover to block these central pathways.......