By Steve Tokar Researchers at the San Francisco VA Medical Center, University of California, San Francisco, and Gladstone Institute of Cardiovascular Disease have uncovered a biochemical signaling pathway that leads to the formation of abnormally large bones in mice. For humans, the discovery may provide clues to both childhood bone formation and osteoporosis -- the loss of bone in old age -- as well as a path to improved osteoporosis treatments. The research is detailed in a paper in the online Early Edition of the Proceedings of the National Academy of Sciences. "We're trying to understand how signaling pathways control bone mass and bone quality," says senior investigator Robert A. Nissenson, PhD, a senior research scientist at SFVAMC and a professor of medicine and physiology at UCSF. "This is critical, since the major defect that occurs in osteoporosis is a deficit in the amount and quality of bone." The researchers used a strain of genetically engineered mouse in which a specially designed hormone receptor activates a signaling pathway called Gs, which is known to affect bone growth. They found that the mice with continuously active Gs signaling in bone developed abnormally large and misshapen bones by the age of nine weeks. "The bones were four to six times larger in cross section than normal -- an absolutely astonishing effect," says Nissenson. The Gs pathway is clinically significant because in osteoblasts -- the cells that create and maintain bone -- it is normally activated by administration of parathyroid hormone (PTH), which is commonly used as a treatment for osteoporosis. "In humans, PTH has to be given as a daily injection, and does not result in a very large increase in bone mass," notes lead author Edward C. Hsiao, MD, PhD, a California Institute of Regenerative Medicine Scholar at the Gladstone Institute of Cardiovascular Disease and an endocrinology fellow at UCSF. "For treating osteoporosis, it would be desirable to optimize this process in order to improve the rate of bone formation." Intriguingly, the researchers observed that when the Gs-activating receptor was kept turned off in the mice until the age of four to six weeks -- when mice reach puberty -- and then turned on, bone development was normal. "This suggests that for this particular receptor, there's a crucial window of time in terms of how and when its activation affects bone growth and development," says Hsiao. "For humans, clinically speaking, this could be very important," Nissenson observes. "Susceptibility to fracture in old age is directly related to bone mass, which reaches a peak at age 30 or so and then slowly declines. If this signaling system could somehow be manipulated in youth, it could be a way of reducing fracture risk later in life." Hsiao cautions that the excess bone formed in the mice is an abnormal type called trabecular bone, which unlike normal skeletal bone is spongy, soft, and lacks a hard outer shell called the cortex. "This is not the ideal type of bone you'd want to grow to treat osteoporosis," he says. "On the other hand, this shows that we are able to increase bone mass using cells already present in the animal. It's possible that by tweaking other systems, we can stimulate the growth of normal skeletal bone." Co-authors of the paper are Benjamin M. Boudignon, PhD, of SFVAMC and UCSF; Wei C. Chang, PhD, of GICD and UCSF; Margaret Bencsik, BA, and Jeffrey Peng, BA, of SFVAMC and UCSF; Trieu D. Nguyen, BA, and Carlota Manalac, BA, of GICD; Bernard P. Halloran, PhD, of SFVAMC and UCSF; and Bruce R. Conklin, MD, of GICD and UCSF. The research was supported by funds from the National Institutes of Health, the California Institute of Regenerative Medicine/J. David Gladstone Institute CIRM Fellowship Program, the Department of Veterans Affairs, the American Heart Association, and the National Center for Research Resources. NCIRE - the Veterans Health Research Institute - is the largest research institute associated with a VA medical center. Its mission is to improve the health and well-being of veterans and the general public by supporting a world-class biomedical research program conducted by the UCSF faculty at SFVAMC. SFVAMC has the largest medical research program in the national VA system, with more than 200 research scientists, all of whom are faculty members at UCSF. The Gladstone Institute of Cardiovascular Disease is one of three research institutes of the J. David Gladstone Institutes, a private, nonprofit biomedical research institution. It is affiliated with UCSF. UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate level education in the life sciences and health professions, and excellence in patient care.