Sci. Aging Knowl. Environ., 7 September 2005
Get Out of the Way
Parathyroid hormone builds more bone when a similar protein is absent
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2005/36/nf71
When a crew builds a house, plumbing installation speeds up if the carpenters get out of the way. Similarly, a bone-manufacturing protein works better in animals that lack another bone molecule, new work reveals. The findings might help researchers fine-tune therapy for osteoporosis patients.
In osteoporosis, the skeleton thins when cells that break down bone--known as osteoclasts--outwork the cells that make it--osteoblasts (see "The Plot Thickens on Thin Bones"). Most drugs battle osteoporosis by squelching osteoclasts; they slow bone loss, but they don't rebuild it. To shore up the skeleton, researchers are seeking drugs that prod osteoblasts to fashion more bone. One such therapy is parathyroid hormone (PTH). PTH normally helps dissolve bone to increase blood-calcium quantities. But when injected daily into patients, the molecule encourages bone growth, perhaps replicating its role in crafting the fetal skeleton. Not everyone responds to PTH therapy, however. To predict who will benefit, researchers want to understand how PTH works. Previously, physiologist David Goltzman of McGill University in Montreal, Canada, and colleagues found that bones thin in mice that have unusually small amounts of PTHrP, a molecule with a similar amino acid sequence to that of PTH. In new work, the scientists investigated why those animals lose bone.
First, they measured the growth rate and composition of the skeleton in animals with only one copy of Pthrp, the gene that encodes PTHrP. The animals created fresh bone more slowly than normal. In addition, their bones contained fewer osteoblasts than did those from normal animals, and more of their osteoblasts were killing themselves. In culture, abnormally few osteoblasts arose from the animals' bone marrow cells. Many types of cells, including osteoblasts, fashion PTHrP, so the researchers determined whether PTHrP produced specifically by bone was vital. They removed both copies of the Pthrp gene from only mouse bone cells. Compared with normal animals, the altered mice had thin bones, made bone slowly, and carried fewer osteoblasts. Together, the findings suggest that stemming osteoblast production of PTHrP weakens bone because animals don't maintain sufficient numbers of the skeleton-building cells. Next, the researchers injected PTH into animals with only one copy of Pthrp. Their bone density increased by a larger amount than in genetically normal animals receiving the shots. If PTHrP works similarly in humans, those whose osteoblasts make small amounts of the hormone might be the ones who build bone when injected with PTH, says Goltzman.
"The major challenge [in PTH therapy] is figuring out who's going to have the best response," says endocrinologist Clifford Rosen of the Maine Center for Osteoporosis Research and Education in Bangor, and this paper provides some of the first clues. Bone researcher Robert Jilka of the University of Arkansas for Medical Sciences in Little Rock notes that PTH might build bone by preventing osteoblast suicide; PTH could work better in animals deficient in PTHrP because it thwarts the rampant osteoblast death seen in those rodents. Researchers should measure cell death in the PTH-treated, PTHrP-deficient animals to test that idea, he says. Those endeavors might reveal how to give PTH the room it needs to construct healthy bone.
September 7, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150