No abstract

Upon the discovery of RANK, RANKL and OPG in the late 1990s, their importance in the maintenance of the skeletal structure and their dramatic role in bone disease were largely unexpected. In recent years the understanding of these proteins, in particular their regulation, has greatly increased. This review aims to bring the interested reader up to date with the latest news and views on the mechanisms controlling bone resorption in normal and pathological conditions.

In 1986 more than 8 million liters of crude oil spilled into a complex region of mangroves, seagrasses, and coral reefs just east of the Caribbean entrance to the Panama Canal. This was the largest recorded spill into coastal habitats in the tropical Americas. Many population of plants and animals in both oiled and unoiled sites had been studied previously, thereby providing an unprecedented measure of ecological variation before the spill. Documenation of the spread of oil and its biological begun immediately. Intertidal mangroves, algae, and associated invertebrates were covered by oil and died soon after. More surprisingly, there was also extensive mortality of shallow subtidal reef corals and infauna of seagrass beds. After 1.5 years only some organisms in areas exposed to the open sea have recovered.

Therapeutic monoclonal antibodies (mAbs) have become one of the fastest growing classes of drugs in recent years and are approved for the treatment of a wide range of indications, from cancer to autoimmune disease. Perhaps the best studied target is the pan B-cell marker CD20. Indeed, the first mAb to receive approval by the Food and Drug Administration for use in cancer treatment was the CD20-targeting mAb rituximab (Rituxan®). Since its approval for relapsed/refractory non-Hodgkin’s lymphoma in 1997, rituximab has been licensed for use in the treatment of numerous other B-cell malignancies, as well as autoimmune conditions, including rheumatoid arthritis. Despite having a significant impact on the treatment of these patients, the exact mechanisms of action of rituximab remain incompletely understood. Nevertheless, numerous second- and third-generation anti-CD20 mAbs have since been developed using various strategies to enhance specific effector functions thought to be key for efficacy. A plethora of knowledge has been gained during the development and testing of these mAbs, and this knowledge can now be applied to the design of novel mAbs directed to targets beyond CD20. As we enter the “post-rituximab” era, this review will focus on the lessons learned thus far through investigation of anti-CD20 mAb. Also discussed are current and future developments relating to enhanced effector function, such as the ability to form multimers on the target cell surface. These strategies have potential applications not only in oncology but also in the improved treatment of autoimmune disorders and infectious diseases. Finally, potential approaches to overcoming mechanisms of resistance to anti-CD20 therapy are discussed, chiefly involving the combination of anti-CD20 mAbs with various other agents to resensitize patients to treatment.