SHIPping Out Bone Breakers
Authors: Davenport R. John 
Published: August 2003

Replacing rotting timbers is crucial to keep a boat afloat, but if the removal crew overwhelms the construction workers, it can sabotage the entire structure. A new study pinpoints a protein that blows the 5 o'clock whistle forthe skeleton's demolition team. The work presents the first indication that the protein governs bone cell formation and should prod scientists to discern whether defects in its ability to call it quits for the wrecking crew contribute to human bone diseases.

Skeletons undergo constant renovation: Osteoclasts tear down bone, whereas osteoblasts rebuild it. But old age, hormone imbalances, and genetic defects can upset the balance between the two cell types. When too many osteoclasts accumulate--as occurs in Paget disease, the most common age-related bone disorder after osteoporosis--bones thin and lose their strength. To get a handle on these conditions, scientists want to understand how osteoclasts develop from precursor cells called macrophages. Researchers had previously identified a protein called SHIP that restrains macrophages from growing and specializing: Mice without the
SHIP
gene accumulate an excess of macrophages.

Takeshita and colleagues wondered whether SHIP also quells osteoclast formation. To address the question, the researchers examined mice that lack the
SHIP
gene. The animals' bones contained twice as many osteoclasts as did bones from control mice. Moreover, cells from the altered animals were larger than normal, resembling those from patients with Paget disease. In addition, their bones showed signs of osteoporosis. The scaffold of bone that fills the interior of the rodents' femurs was thinner and contained larger holes (see
Osteoporosis Images
) than in normal bone. Without
SHIP
, bones also bent and broke unusually easily. Together, the results suggest that SHIP normally restrains osteoclast formation and prevents bone destruction.

Cell culture studies support that conclusion. The researchers extracted macrophages from the altered animals and exposed them to two signaling molecules known to spur osteoclast formation. Macrophages that lack SHIP were more likely to morph into osteoclasts than were control cells; the resulting osteoclasts also survived longer and displayed greater bone-obliterating power. Previous work showed that SHIP deactivates a molecule called PIP
3
, which relays the message sent by two molecules that promote osteoclast formation. By inhibiting PIP
3
, SHIP blocks the conversion of macrophages into osteoclasts and prevents bone loss, suggests co-author and immunologist F. Patrick Ross of Washington University in St. Louis, Missouri.

The discovery of SHIP's role in bone remodeling is "brand-new," says bone biologist G. David Roodman of the University of Pittsburgh. Scientists had previously discovered SHIP's ability to hinder blood cell specialization, but "no one knew [that] it had any importance [for bone] until now." It's too early to tell whether SHIP defects contribute to Paget disease, he says, although the authors note that the human
SHIP
gene resides in a chromosome region that is altered in some families afflicted with the disorder. Regardless, the new work should help scientists understand why the body sometimes fails to keep its bones shipshape.

--R. John Davenport

S. Takeshita, N. Namba, J. J. Zhao, Y. Jiang, H. K. Genant, M. J. Silva, M. D. Brodt, C. D. Helgason, J. Kalesnikoff, M. J. Rauh, R. K. Humphries, G. Krystal, S. L. Teitelbaum, F. P. Ross, SHIP-deficient mice are severely osteoporotic due to increased numbers of hyper-resorptive osteoclasts.
Nat. Med.
, 5 August 2002 [e-pub ahead of print].
[Abstract/Full Text]