Feb. 24, 2004 A new study by researchers at San Francisco VA Medical Center (SFVAMC) moves in on the physiological basis for the bone density loss experienced by people subjected to prolonged periods of bed rest and by astronauts who fly lengthy missions under the weightless conditions of space.
The work, conducted in rats, is an important step toward developing therapies to prevent such bone loss, says senior author Daniel Bikle, MD, co-director of the Special Diagnostic and Treatment Unit at SFVAMC and professor of medicine and dermatology at University of California, San Francisco. Lead author of the study is Takeshi Sakata, who was a postdoctoral fellow in Dr. Bikle's laboratory at the time of the study and is now an orthopedic surgeon at the Kitade Hospital in Gobo, Wakayama, Japan.
The current study builds on animal work Bikle and Sakata published last year, which showed that when bones are relieved of the burden of bearing weight, bone precursor cells fail to respond to insulin-like growth factor one or IGF-I, a biochemical regulator that plays a key role in the proliferation of most cell types. Now Bikle and his team have found that this lack of response occurs because IGF-I does not activate its receptor molecule on the surface of the cells. In addition, the researchers found that the interaction failure is probably triggered by a loss of integrins, proteins found in the membranes of bone cells that enable these cells to sense mechanical changes in their immediate environment. These integrins are also known to regulate the action of growth factors in other cells. The study appears in the March issue of the Journal of Bone and Mineral Research.
"Up until now, researchers have not demonstrated this signaling feedback loop in bone," says Bikle. "But it makes sense: Integrins are mechano-sensors. When the bone is moving and bearing weight, the integrins initiate a signaling process within the cell. This signal, in turn, impacts IGF-I's ability to activate its receptor signaling system inside the cell."
When a limb is immobilized in a cast, when an astronaut experiences zero gravity, or whenever a person lies down, the weight-bearing bones of the body such as those in the spine and leg, are relieved of their burden, a condition known as skeletal unloading. When skeletal unloading persists for several weeks, bones start to deteriorate: the number of bone cells decreases, movement into the bone of such minerals as calcium and phosphorus slows, and production of bone-cell precursors called osteoprogenitor cells diminishes. All these changes result in weakened, brittle bones prone to fracture.
While the bones of children may be able to eventually recover from such changes, adult bones have a harder time of it. Studies of Skylab and Salyut-6 long-term space missions (28-184 days) have found that, not only did astronauts on board the craft lose bone density during their missions, but five years later they had failed to recover to pre-launch bone density levels.
"The big problem that NASA is facing in their plans to send a manned flight to Mars is how to get people there and back without having their skeletons turn to matchsticks," Bikle says. "Yet discovering a way to stop bone loss from skeletal unloading will impact more than just a few astronauts. Anyone who is immobilized in any way for a long period of time can benefit."
To track the mechanism of bone loss, Bikle and his team devised a way of taking the weight off a rat's hindquarters while maintaining normal weight and movement in the animal's front legs. With hindquarters suspended by a freely moving line tethered to the cage lid (much like the pole that connects a bumper-car to the ceiling, allowing it to move anywhere on the floor), the rats moved around, groomed, ate and otherwise managed with just their forelimbs in the same way as their untethered companions during the 14-day trial period. The research team observed the animals carefully for symptoms of stress and also analyzed blood samples for stress hormones, but found no indications of stress in either the skeletal unloaded rats or their untethered companions.
In order to be able to follow IGF-1 pathways, the team used a special line of dwarf laboratory rats that do not produce their own growth hormone. Half the animals in both the tethered and untethered groups were given IGF-1, while all rats in both groups were injected with a compound that traces actively dividing cells. At the end of the trial period, the team found that the numbers of precursor bone cells in the forelimbs of rats that had received IGF-1 was double that of rats that had not received the growth factor. But in the "unloaded" hind limbs, cell division was virtually stalled, regardless of whether animals had received the growth factor or not.
The team then cultured cells from loaded and unloaded bones and put the cells through numerous biochemical assays looking for the point in the bone formation pathway that is blocked when bones are unloaded. They found that while IGF-I bound normally to its receptor, activation of the receptor did not take place. This activation is required for IGF-I to stimulate cells to grow. Bikle and his team then found that this same inhibition of the ability of IGF-I to activate its receptor could be duplicated by inhibiting integrin function. This fit neatly into their observation that integrin levels were reduced by skeletal unloading, These observations link the loss of integrins to the failure of IGF-I to activate its receptor.
"The next step," Bikle says, "is to determine what's impeding production of integrin during skeletal unloading, and what the mechanism is that links the integrin signaling pathway to the IGF-I receptor activation. Once we understand these processes, we'll have some targets that we can address to help us devise interventions to prevent bone loss from skeletal unloading." Based on his current findings, Bikle speculates that such interventions will be based either on finding a way to reproduce the beneficial effects of integrin signaling, or of figuring out how to bypass the signaling pathway that is initiated by the interaction of IGF-I and its receptor.
Other authors of the study are Yongmei Wang, MD, PhD, postdoctoral fellow in endocrinology at SFVAMC and in medicine at UCSF; Bernard Halloran, PhD, biochemist in endocrinology at SFVAMC and adjunct professor of endocrinology at UCSF; Hashem Z. ElAlieh, BS, research associate in endocrinology at SFVAMC, and Jay Cao, PhD, postdoctoral fellow in endocrinology at SFVAMC and UCSF.
The study was funded by grants from NASA and the National Institutes of Health to NCIRE, the Northern California Institute for Research and Education.
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