Since loss of LRP5 causes brittle bones and people with overactive LRP5 build extra bone, drugs that boost LRP5 activity could boost bone growth without keeping damaged bone from being recycled. This is why Warman says that “LRP pathways in bone are very exciting targets.”

Warman has studied bone building in patients who make too much bone to better understand—and ultimately enhance—bone building. What happens in these patients resembles an extreme version of what happens during weight-bearing exercise like hiking or weight lifting, which spurs the body to bolster bone where it’s needed. (In a famous 1977 study, the upper arm bones of professional tennis players were 30 percent thicker in the arm they used to hit the ball than in their other arm.)

Recently, Warman’s team engineered mice to produce the overactive version of Lrp5 but only in mature osteocytes in hard bone. Osteocytes are believed to sense mechanical stress and release compounds that recruit osteoblasts to lay down more bone. Warman’s collaborator, Robling at Indiana University, anesthetized the mice and then mimicked the effects of weight-bearing exercise by repeatedly bending their forelimbs. Mice with overactive Lrp5 in their osteocytes produced three times more bone than normal mice put through the same exercises.

“That tells us that the high bone mass mutation works in very mature bone cells,” Warman says. “And, if we can think of a way to make an LRP5 receptor in mature bone cells think that it has a high bone mass mutation, then you and I can have more bone.” At least three companies have looked for and found a compound that tricks the LRP5 receptor in just this way. For example, Amgen is running phase 2 clinical trials on its version of an antibody to sclerostin. Eli Lilly and Company has developed a chemical compound that keeps sclerostin from blocking LRP5.

Warman is eager to develop bone-building drugs to help some of his youngest patients—children with osteogenesis imperfecta. This hereditary disease can kill before birth or make children so susceptible to fractures that they must spend their lives in a wheelchair, Warman says.

As Warman’s team tries to build bone by targeting LRP5 in bone cells, Karsenty’s team is trying to build it by blocking production of a compound called serotonin in the gut. In 2008, his team found to their surprise that LRP5 blocks gut cells from producing serotonin, which normally signals bone-building cells to stop multiplying. Last year, they reported in Nature Medicine that a drug that blocks serotonin synthesis in the gut builds bone in mice. The results seem to conflict with Warman’s, but “it’s possible that both groups are in part correct, and more needs to be done to sort out that whole story,” Khosla says.

		A Local Effect on Bone Mass Learn more about Matt Warman’s research. Read More

While most researchers seeking bone-building drugs have targeted Wnt signaling, including LRP5, HHMI investigator Gerald Crabtree, at Stanford University, has discovered a second pathway that seems to help the body build bone. A few years ago, Monte Winslow, an HHMI predoctoral fellow in Crabtree’s lab, was investigating why the anti-rejection drug cyclosporine causes bone loss. They knew that cyclosporine indirectly changes the shape of a protein called NFATc that typically sits in the cell’s cytoplasm but moves into the nucleus to activate genes.

When they engineered mice with a mutant version of NFATc that stays in the nucleus just 10 percent longer, the result was “the boniest mouse anyone ever produced,” Crabtree says. Unlike a normal mouse, which feels “soft and cuddly,” Crabtree says, these mice “felt like a bag of bones.” Now, he and biochemist and HHMI investigator Stuart Schreiber of Harvard University are hunting for chemical compounds that tweak normal NFATc to act like the nucleus-loving version. Such compounds will shed light on how the NFATc pathway leads to bone growth and, with luck, may lead to drugs that boost bone growth in a new way.

Immature Bone and Cancer

Sometimes bones lose their balance by overgrowing and becoming cancerous. Brendan Lee, a pediatric geneticist and HHMI investigator at Baylor College of Medicine in Houston, pursues therapies for osteosarcoma, the most common type of cancer that originates in the bones, from which about 60 percent of patients recover. To do so, he draws on insights gained by treating patients with hereditary bone, cartilage, and joint diseases at the Skeletal Dysplasia Clinic at Texas Children’s Hospital.

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