Sci. Aging Knowl. Environ., 14 May 2003
Vol. 2003, Issue 19, p. nw68
[DOI: 10.1126/sageke.2003.19.nw68]


Reduced Renewal

Meager stem cell cache thins bones in mutant mice

R. John Davenport;2003/19/nw68

Key Words: Ly-6 • hematopoietic stem cell • mesenchymal stem cell • DEXA

Without a steady supply of workers, a construction project falls behind schedule, whether it's a skyscraper or a skeleton. Mice that lack a crucial stem cell protein lose bone-building cells and, as a consequence, develop osteoporosis, according to new work. The animals provide a new way to study age-related bone loss and might lead researchers to treatments that bolster bone by prodding precursor cells to divide.

The most familiar type of osteoporosis is linked to menopause (see "More Than a Hot Flash"), but another form of the disease also occurs. After age 70, men and women can suffer a gradual bone decay that boosts the risk of fractures, predominantly in the hip and spine. Both varieties of osteoporosis reflect a shift in the numbers and activities of cells that reshape bone. Normally, bone demolishers called osteoclasts and bone-building cells called osteoblasts collaborate to replace fatigued bone with fresh tissue. But when osteoclasts overpower osteoblasts, bone thins and weakens. Researchers understand much about how the balance goes awry in postmenopausal osteoporosis (see "The Plot Thickens on Thin Bones"), but changes that underlie age-related osteoporosis remain more mysterious.

While studying mice that lack a cell surface protein called Sca-1--which is important for maintaining blood stem cells--geneticist William Stanford of the University of Toronto in Canada and colleagues discovered that the animals had weak bones. At first, the problem merely hindered the team's attempts to collect bone marrow, Stanford says, but then he wondered, "Could we have an osteoporotic mouse?"

To find out, the team measured bone density in mutant and normal animals. Young rodents without Sca-1 had bones of normal density, but by 12 months of age, the mutants' bones were less compact than those of control animals. Furthermore, they broke more easily.

Analysis of femurs from mutant mice revealed less new bone than in normal mice, implying that osteoblast numbers or activity had plunged. Additional experiments suggested that a dearth of Sca-1 hinders rodents' ability to maintain a supply of osteoblast precursors. Bone marrow from mutant mice carried fewer osteoblast progenitor cells and didn't produce as many bonemaking cells as did marrow from normal animals. Moreover, the mutants carried fewer mesenchymal stem cells--from which osteoblast progenitor cells and thus osteoblasts originate--and the number of these cells plummeted as animals aged.

Other studies have produced mice that mimic age-related osteoporosis, but this work is the first to implicate a single gene, says bone biologist Robert Jilka of the University of Arkansas, Little Rock. But bone biologist Steven Teitelbaum of Washington University in St. Louis, Missouri, cautions that whether the mouse faithfully re-creates the human disease is unclear. "Chances are very good that [age-related] osteoporosis results from a defect in this cell lineage, but whether this particular genetic change is involved is unknown--we just don't know what causes the human disease." Still, understanding how the body maintains it's supply of future bone workers might reveal new ways to keep bone construction from falling behind in old age.

--R. John Davenport

May 14, 2003
  1. M. Bonyadi et al., Mesenchymal progenitor self-renewal deficiency leads to age-dependent osteoporosis in Sca-1/Ly-6A null mice. Proc. Natl. Acad. Sci. U.S.A., 5 May 2003 [e-pub ahead of print]. [Abstract] [Full Text]
Citation: R. J. Davenport, Reduced Renewal. Sci. SAGE KE 2003, nw68 (14 May 2003);2003/19/nw68

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