Sci. Aging Knowl. Environ., 28 April 2004
Bad to the Bone
Proteins that build skeletons in embryos promote bone loss in the aged
A turncoat lurks in the elderly skeleton. New research shows that proteins that build bone during youth promote its destruction later in life by prodding bone-dissolving cells into action. The results could lead to treatments to strengthen aging bone and fight diseases such as osteoporosis.
Bone is constantly undergoing renovation. Cells called osteoclasts tear it down, and cells called osteoblasts rebuild it. The two cell types collaborate, with osteoblasts activating osteoclasts. For unknown reasons, the balance between demolition and renovation shifts in diseases such as osteoporosis, resulting in dire weakening of bones (see "The Plot Thickens on Thin Bones"). Bone morphogenetic proteins (BMPs) stimulate osteoblasts and help orchestrate bone formation before birth, and many researchers suspect that they also fortify the adult skeleton. But determining their roles has been difficult because disabling genes for the proteins or their receptors throughout the body kills mice before birth.
So molecular geneticist Yuji Mishina of the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina, and colleagues shut down one BMP receptor gene, Bmpr1a, only in osteoblasts of newborn mice. The engineered rodents grew sluggishly and made bone more slowly than did normal mice. Their bones were also thinner than those of controls. When the researchers reared osteoblasts from both groups, they found that cultures from altered mice carried less of a protein found in mature osteoblasts and produced smaller amounts of the minerals that harden bone. Together, these results suggest that disrupting BMPs weakens the skeleton by hampering osteoblasts' bone-building activities.
The situation reversed after the mice reached middle age. Skeletons of 10-month-old engineered mice showed higher bone-mineral density, a gauge of strength, than did the skeletons of controls. The altered rodents also sported thicker bones than their normal counterparts did. The researchers suspected that bone-dissolving osteoclasts might falter in engineered older animals. To test the idea, they cultivated altered and control bone cells and goaded them with a BMP that activates the BMPRIA receptor. The treatment spurred control cultures to pump out extra quantities of three osteoclast-produced enzymes. Cultures lacking the receptor didn't increase their output. Because only osteoblasts lacked the receptor, these results indicate that BMPs act on osteoclasts through osteoblasts. The findings suggest that the BMPs change function with age. In youth, they spur osteoblasts to make bone. Later in life, they stimulate osteoblasts to rouse osteoclasts, resulting in bone deterioration. By suggesting that compounds that bump up BMPs could speed bone loss in old age, the results might help drug designers craft more effective treatments for osteoporosis, Mishina says.
The study indicates "important communication between osteoblasts and osteoclasts," says bone biologist Xu Cao of the University of Alabama, Birmingham. Bone specialist Edward Puzas of the University of Rochester School of Medicine and Dentistry in New York says, "It's important work. We haven't appreciated the pervasive effects of BMPs on skeletal formation." Now, he says, researchers need to figure out how BMPs produce different outcomes at different ages. That work might reveal how to stop BMPs from becoming the bone's Benedict Arnold.
April 28, 2004
Suggested by Jennifer Fuller.
Science of Aging Knowledge Environment. ISSN 1539-6150