Bone resorption cells offer drug targets for osteoporosis, rheumatoid arthritis, and moreWashington University pathologist Dr. Steven Teitelbaum describes how he and his colleagues are using their understanding of the role of osteoclasts to develop therapeutic targets for osteoporosis and the bone loss around joints in rheumatoid arthritis. Dr. Teitelbaum was a member of the team that first recognized the cause, then cured osteopetrosis (a fatal disease of the osteoclast cells that absorb bone) in an infant. The infant was cured by a bone marrow transplant that gave her normal bone resorbing cells, but the Teitelbaum group's understanding of how the osteoclasts worked opened the door to development of drugs, such as Fosamax, that inhibit these cells and thus diminish the rate of bone degradation.
To honor this and other ongoing work, Dr. Teitelbaum is the recipient of this year's Rouse Whipple Award, presented by the American Society for Investigative Pathology (ASIP) to a pathologist with an illustrious career in research and continued productivity in the field. His Rouse Whipple Award Lecture on April 3 at the Experimental Biology 2006 meeting in San Francisco is part of ASIP's scientific program.
Bone is continuously broken down (resorbed) by osteoclasts and formed by another type of cells, the osteoblasts. Osteoporosis occurs when the rate of bone resorption surpasses that of bone formation. Dr. Teitelbaum has spent his career trying to understand the precise details of how osteoclasts work, with a recent focus on the discovery, by Dr. Teitelbaum and his colleague F. Patrick Ross, that the bone degrading capacity of osteoclasts depends upon their physical interaction with receptor proteins on the bone surface. Blocking these receptors, known as integrins, also prevents osteoporosis, as demonstrated when mice bred by the researchers to lack genes for the major integrins develop increased bone mass.
Developing drugs that focus on inhibiting the effect of integrins on the osteoclasts has potential advantages, says Dr. Teitelbaum. The popular anti-osteoporosis drug Fosamax works – and quite effectively – by inhibiting the osteoclasts. But the drug is stored in the skeleton for long periods of time and adverse effects in chronic users now are being encountered. Phase 2 clinical trials in humans are now underway for drugs that target the integrins, and Dr. Teitelbaum is hopeful these new drugs will bypass such problems.
In addition to the osteoporosis that often occurs in the aging process, Dr. Teitelbaum's group has made great advances in understanding bone loss in three other diseases.
Rheumatoid arthritis. The crippling bone loss that occurs around joints in people with rheumatoid arthritis is caused by the interaction of osteoclasts and the inflammatory cytokines produced by the immune system. Dr. Teitelbaum's group has identified many of the indirect and direct means by which these cytokines cause joint destruction – and are pinpointing targets for drugs to prevent this loss.
HIV/AIDS. In recent years, scientists have documented that some of the protease inhibitor drugs that have had such a dramatic effect lowering the viral load in patients with HIV/AIDS have also had an effect on the osteoclast, causing changes in bone mass in patients taking these drugs. Dr. Teitelbaum's laboratory has documented specific proteases that have different effects on the osteoclasts, suggesting that changing the protease inhibitor being given might diminish bone loss, or that patients on protease inhibitor drugs may need to take antiosteoporosis drugs as well.
Cortisone-induced osteoporosis in transplant recipients, asthma, lupus, inflammatory diseases and other diseases requiring use of cortisone for therapy. Taking cortisone can lead to bone loss, with as much as 12 percent skeleton loss the first year and continuing loss of approximately 3 percent per year, says Dr. Teitelbaum. His laboratory has discovered novel mechanisms of how cortisone suppresses the osteoclast, which then leads to suppression of the cells that create new bones. Because cortisone-induced osteoporosis is such a common form of osteoporosis, much more research is needed in this area, says Dr. Teitelbaum.
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