Learning How to Control Cells That Remodel and Destroy Bone
The number of Americans stricken by a deadly and debilitating bone-thinning disease continues to climb. According to a 2004 Surgeon General's report, more than half of Americans age 50 and older are at risk for osteoporosis - porous bones.
But pioneering researchers called osteoimmunologists - a small, but fast-growing group that just convened its first-ever international meeting in June - may help turn the tide against the disease.
The human skeleton is not just a mineralized structural support; it's living tissue with its own cells. Scientists are discovering that immune cells and bone cells influence one another much more strongly than had previously been suspected. Osteoimmunologists are a new breed of scientific experts who investigate this cross talk.
Osteoimmunologists are gaining insights into how bones are built up and broken down in health, disease and aging. The hope is that new knowledge will lead to new preventive strategies and treatments - not only for osteoporosis, but also for rheumatoid arthritis, osteoarthritis and other inflammatory diseases in which chronic immune system activity is associated with bone loss. In fact, some potential therapies based on recent years' discoveries are already in clinical trials.
Build, Tear Down, Rebuild
Two types of cells are especially critical to developing and maintaining healthy bones. One type of cell, called the osteoclast, breaks down and resorbs mineralized bone. It is a key to bone remodeling and repair during early development and throughout life. Osteoclasts clear the way for another type of cell - the osteoblast. The osteoblast builds new bone. Osteoclasts and osteoblasts normally are in balance. But to treat diseases that result in bone loss, pharmaceutical companies are making efforts to specifically target bone-resorbing osteoclasts to halt or reverse the loss. "Osteoclasts really are the only bone-resorbing cells in the body," says UCSF researcher Mary Beth Humphrey, MD, PhD. "They are important for maintaining bones day to day. Everybody undergoes a little bone remodeling daily." As a physician at the San Francisco Veterans Affairs Medical Center (SFVAMC) and UCSF Medical Center, Humphrey cares for patients with debilitating rheumatoid arthritis and other inflammatory diseases. But as a doctoral scientist, she is probing down to the marrow and beyond to find the biological mechanisms underlying diseases of bone loss. Her focus is on learning more about the molecular interactions that cause osteoclasts to develop and to perform specific functions. There are only a handful of US laboratories - and several more abroad - that focus on the study of osteoclasts and their signaling molecules. However, osteoclasts may be the key to improved therapies, Humphrey suggests. "One could envision targeting molecules in a way that would shut down a subset of mature osteoclasts - stopping bone erosion without a lot of side effects," she says. Recent Changes in Treatment, with More to Come
In fact, drug companies are taking steps in that direction. But researchers have much to learn about the biochemistry of bone thinning, and even about the mechanisms of treatments that have long been in use. Estrogen in women has long been known to help maintain bone strength. Until a few years ago, an estrogen hormone, usually coupled with a progestin hormone, was widely prescribed to postmenopausal women to prevent bone loss. Then the massive Women's Health Initiative study revealed that estrogen poses risks of cancer and atherosclerotic disease. About a decade ago, another class of drugs called bisphosphonates became available. Like estrogen, bisphosphonates have been shown to prevent bone loss in clinical trials. In some cases, bisphosphonate therapy may slightly reverse bone loss, at least in the short term. Some patients - including those with poor kidney function - do not tolerate them. As with estrogen and its mimics, the biochemical mechanisms underlying these effects are not entirely clear, although bisphosphonates are known to hinder the actions of osteoclasts. Parathyroid hormone therapy and similar treatments, which stimulate osteoblasts to make new bone, also have reached the drug marketplace in recent years. But animal studies have now raised questions about possible bone cancer risks. When used, treatment time with parathyroid hormone is restricted. New Generation of Designer Drugs Enters Clinical Trials
The newest pharmaceuticals to be evaluated in clinical trials are "designer" drugs targeted to specific molecules known to play a role in bone resorption or formation. In February, the New England Journal of Medicine published results of a clinical trial on an Amgen drug called denosumab, which was evaluated in more than 400 postmenopausal women with low bone density. After a year's treatment, the study team reported that denosumab increased bone density more than an already-approved bisphosphonate. Women in the study who took a placebo lost bone. Denosumab is an antibody that attaches and ties up a molecule called RANKL. RANKL normally binds to a receptor on osteoclast progenitor cells. When RANKL binds, it causes immature osteoclasts to mature into cells capable of resorbing bone when activated. Denosumab prevents RANKL from binding to immature osteoclasts, so that the cells cannot mature and become activated. While denosumab is better targeted than some other experimental therapies, Humphrey and other osteoimmunologists wonder about potential long-term side effects. That's because the RANKL molecule also is present on important types of immune cells, raising the possibility that treatment may compromise immune responses. UCSF Research Discoveries
Humphrey collaborates with renowned UCSF immunologist Lewis Lanier, PhD, and she trained in the laboratory of Mary Nakamura, MD, a rheumatologist and an associate professor of medicine at UCSF. Humphrey continues to collaborate and share a lab with Nakamura at the SFVAMC. Humphrey and colleagues have discovered that other molecules appear to play more specific roles in osteoclast development and activity. Even so, in a general way, the signaling molecules they have described in osteoclasts are like molecules that play similar roles in some types of cells of the immune system - highlighting how closely these cells are related. It turns out that the binding of RANKL to the cell is not the only event required for osteoclast maturation. One molecule identified by the UCSF researchers is a receptor, called TREM2, that sits on the surface of the osteoclast. When the receptor is activated (it is not yet clear how), a signal is relayed into the osteoclast by a membrane-spanning "adapter" protein called DAP12. In a chain reaction, a signaling cascade within the cell then triggers the osteoclast to mature. "Our studies to date reveal that DAP12 signaling is required for normal osteoclast development in vitro," Humphrey says. "Furthermore, mice that are genetically deficient in DAP12 have increased bone mass, secondary to decreased activity of osteoclasts." The TREM2 receptor or the molecules that activate the receptor might be good, specific targets to curtail osteoclast activity and bone loss in osteoporosis or inflammatory diseases, she suggests.
Two types of cells are especially critical to developing and maintaining healthy bones. One type of cell, called the osteoclast, breaks down and resorbs mineralized bone. It is a key to bone remodeling and repair during early development and throughout life. Osteoclasts clear the way for another type of cell - the osteoblast. The osteoblast builds new bone. Osteoclasts and osteoblasts normally are in balance. But to treat diseases that result in bone loss, pharmaceutical companies are making efforts to specifically target bone-resorbing osteoclasts to halt or reverse the loss. "Osteoclasts really are the only bone-resorbing cells in the body," says UCSF researcher Mary Beth Humphrey, MD, PhD. "They are important for maintaining bones day to day. Everybody undergoes a little bone remodeling daily." As a physician at the San Francisco Veterans Affairs Medical Center (SFVAMC) and UCSF Medical Center, Humphrey cares for patients with debilitating rheumatoid arthritis and other inflammatory diseases. But as a doctoral scientist, she is probing down to the marrow and beyond to find the biological mechanisms underlying diseases of bone loss. Her focus is on learning more about the molecular interactions that cause osteoclasts to develop and to perform specific functions. There are only a handful of US laboratories - and several more abroad - that focus on the study of osteoclasts and their signaling molecules. However, osteoclasts may be the key to improved therapies, Humphrey suggests. "One could envision targeting molecules in a way that would shut down a subset of mature osteoclasts - stopping bone erosion without a lot of side effects," she says. Recent Changes in Treatment, with More to Come
In fact, drug companies are taking steps in that direction. But researchers have much to learn about the biochemistry of bone thinning, and even about the mechanisms of treatments that have long been in use. Estrogen in women has long been known to help maintain bone strength. Until a few years ago, an estrogen hormone, usually coupled with a progestin hormone, was widely prescribed to postmenopausal women to prevent bone loss. Then the massive Women's Health Initiative study revealed that estrogen poses risks of cancer and atherosclerotic disease. About a decade ago, another class of drugs called bisphosphonates became available. Like estrogen, bisphosphonates have been shown to prevent bone loss in clinical trials. In some cases, bisphosphonate therapy may slightly reverse bone loss, at least in the short term. Some patients - including those with poor kidney function - do not tolerate them. As with estrogen and its mimics, the biochemical mechanisms underlying these effects are not entirely clear, although bisphosphonates are known to hinder the actions of osteoclasts. Parathyroid hormone therapy and similar treatments, which stimulate osteoblasts to make new bone, also have reached the drug marketplace in recent years. But animal studies have now raised questions about possible bone cancer risks. When used, treatment time with parathyroid hormone is restricted. New Generation of Designer Drugs Enters Clinical Trials
The newest pharmaceuticals to be evaluated in clinical trials are "designer" drugs targeted to specific molecules known to play a role in bone resorption or formation. In February, the New England Journal of Medicine published results of a clinical trial on an Amgen drug called denosumab, which was evaluated in more than 400 postmenopausal women with low bone density. After a year's treatment, the study team reported that denosumab increased bone density more than an already-approved bisphosphonate. Women in the study who took a placebo lost bone. Denosumab is an antibody that attaches and ties up a molecule called RANKL. RANKL normally binds to a receptor on osteoclast progenitor cells. When RANKL binds, it causes immature osteoclasts to mature into cells capable of resorbing bone when activated. Denosumab prevents RANKL from binding to immature osteoclasts, so that the cells cannot mature and become activated. While denosumab is better targeted than some other experimental therapies, Humphrey and other osteoimmunologists wonder about potential long-term side effects. That's because the RANKL molecule also is present on important types of immune cells, raising the possibility that treatment may compromise immune responses. UCSF Research Discoveries
Humphrey collaborates with renowned UCSF immunologist Lewis Lanier, PhD, and she trained in the laboratory of Mary Nakamura, MD, a rheumatologist and an associate professor of medicine at UCSF. Humphrey continues to collaborate and share a lab with Nakamura at the SFVAMC. Humphrey and colleagues have discovered that other molecules appear to play more specific roles in osteoclast development and activity. Even so, in a general way, the signaling molecules they have described in osteoclasts are like molecules that play similar roles in some types of cells of the immune system - highlighting how closely these cells are related. It turns out that the binding of RANKL to the cell is not the only event required for osteoclast maturation. One molecule identified by the UCSF researchers is a receptor, called TREM2, that sits on the surface of the osteoclast. When the receptor is activated (it is not yet clear how), a signal is relayed into the osteoclast by a membrane-spanning "adapter" protein called DAP12. In a chain reaction, a signaling cascade within the cell then triggers the osteoclast to mature. "Our studies to date reveal that DAP12 signaling is required for normal osteoclast development in vitro," Humphrey says. "Furthermore, mice that are genetically deficient in DAP12 have increased bone mass, secondary to decreased activity of osteoclasts." The TREM2 receptor or the molecules that activate the receptor might be good, specific targets to curtail osteoclast activity and bone loss in osteoporosis or inflammatory diseases, she suggests.