Sci. Aging Knowl. Environ., 2 October 2002
Vol. 2002, Issue 39, p. nw135
[DOI: 10.1126/sageke.2002.39.nw135]

NOTEWORTHY ARTICLES

For Wnt of Bone

Signaling pathway stems age-related bone loss

R. John Davenport

http://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/39/nw135

Key Words: Frizzled • Wingless • {beta}-catenin • lrp-5

Abstract: SAN ANTONIO, TEXAS--Make no bones without it: The Wnt signaling pathway bulks up the skeleton. New research presented here 21 September 2002 at the 24th Annual Meeting of the American Society for Bone and Mineral Research reveals that an inhibitor of the signal might spur age-related bone loss in mice. The work emphasizes the importance of the pathway in bone renewal and could represent a new target for drugmakers.

Although the skeleton might appear static, it undergoes constant renewal to maintain its strength. Cells called osteoclasts break down bone, and osteoblast cells rebuild it. When these opposing processes aren't balanced, osteoporosis and other bone diseases can result. Studies in the past year have revealed that a molecular signaling pathway called Wnt, previously known to direct the development of body segments and limbs, also regulates bone renewal. People with osteoporosis-pseudoglioma syndrome--an inherited disorder that results in thin, weak bones with a high fracture risk--carry a mutation that inactivates the cell surface receptor that normally binds Wnt protein and activates the pathway (see "Skeleton Crew"). In addition, a mutation that puts the receptor into overdrive is common in families whose members tend to have abnormally high bone mass. Bodine and colleagues discovered last year that bone cells produce a protein called sFRP-1 that thwarts the pathway in other tissues.

To investigate whether sFRP-1 blocks Wnt's skeleton-building signal as well, the researchers generated mice that lack the sFRP-1 gene. Whereas many such manipulations of skeletal genes severely disrupt embryonic development, these mutant animals reached adulthood and were able to breed. Moreover, the rodents' blood carried normal amounts of molecules that indicate bone growth. Like their siblings without the genetic disruption, the mice had bone that reached normal density by 20 weeks of age. Unaltered animals began to lose bone density after that time, but mice without sFRP-1 maintained robust skeletons even at 35 weeks of age. Moreover, the difference was due to an increase in density of trabecular bone, the type lost in osteoporosis. The results suggest that sFRP-1 contributes to bone loss in advancing years.

Additional experiments showed that the mutant animals harbor fewer dying bone cells than do normal animals. In culture, osteoblast precursor cells from the mutant animals more frequently morphed into osteoblasts in response to chemical cues than did cells from control animals. Also, the altered cells laid down more bonelike minerals in culture. Together, the results suggest that by obstructing the Wnt pathway, sFRP-1 blocks bone-constructing cells and that its absence prevents age-related bone deterioration, at least in rodents.

The study "brings the Wnt pathway into focus" for bone researchers, says molecular biologist Matthew Gillespie of the University of Melbourne in Australia. Because lack of sFRP-1 delays bone loss in mice, he wonders whether amounts of sFRP-1 rise when estrogen amounts fall, a primary risk factor for osteoporosis in women. Small molecules that neutralize sFRP-1 might help people lose no bone before its time.

--R. John Davenport

P. Bodine, W. Zhao, Y. Kharode, L. Borella, F. Bex, A. Lambert, M. Goad, G. Stein, J. Lian, B. Komm, Targeted disruption of secreted frizzled-related protein (sFRP)-1 in mice leads to decreased osteoblast and osteocyte apoptosis and increased trabecular bone formation. American Society for Bone and Mineral Research, 24th Annual Meeting, 20 to 24 September 2002, San Antonio, Texas. [Society Home Page]

Citation: R. J. Davenport, For Wnt of Bone. Science's SAGE KE (2 October 2002), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/39/nw135








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