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Key Bone Building Pathway Identified in Mice

January 21, 2008
News Office: Steve Tokar (415) 502-6397

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, 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 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 Dr. Edward C. Hsiao, 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.



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, of SFVAMC and UCSF; Wei C. Chang, of GICD and UCSF; Margaret Bencsik and Jeffrey Peng of SFVAMC and UCSF; Trieu D. Nguyen and Carlota Manalac of GICD; Bernard P. Halloran, of SFVAMC and UCSF; and Dr. Bruce R. Conklin, of GICD and UCSF.






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