A type of cell overlooked by scientists appears to play a critical role in preventing osteoporosis, a condition that affects an estimated 25 million women in the United States.
The discovery, the scientists say, should raise the research profile of the cells, called preosteoclasts. It also explains the success of an experimental osteoporosis drug that has had promising results in clinical trials.
A summary of the new research, conducted using mice with a bone condition similar to osteoporosis, has been published in the journal Nature Medicine.
“We didn’t know that the drug affects preosteoclasts, nor did we understand how important preosteoclasts are in maintaining healthy bones,” says study leader Xu Cao, professor of orthopedic surgery at the Johns Hopkins University School of Medicine. “Now drug companies hoping to reverse osteoporosis can look for even more drugs that make use of and target these interesting cells.”
Calcium and bones
The bones of mice, people, and all land animals are not only necessary for strength and structure, but also as warehouses for calcium. Cells throughout the body use the chemical element continuously for everyday tasks like cell-to-cell communication, muscle strength, and even embryo fertilization and hormone balance.
Calcium is taken from digested food and stored in semi-hollow spaces inside bones. To access the stored calcium, the inner bone goes through a process called resorption, in which cells called osteoclasts attach to the bone and dissolve the calcium and other stored minerals.
Specialized blood vessels nearby pick up the calcium and send it throughout the body. They also bring in nutrients needed for new bone formation.
Under normal conditions, bone resorption is carefully balanced with bone rebuilding to maintain bone strength. But in women who have entered menopause, decreases in estrogen can cause bone resorption to outpace bone rebuilding, leading to osteoporosis and frequent bone breaks.
“Most osteoporosis drugs on the market slow down bone resorption but do nothing to encourage bone rebuilding,” Cao says.
Previous data, including that from early clinical trials in humans, indicated that the drug odanacatib decreases bone resorption by hobbling CTSK, one of the enzymes used to resorb bone. What came as a pleasant surprise was that the same drug also increased bone rebuilding. The question was: How?
Why preosteoclasts matter
To learn more, Cao and his team studied mice genetically engineered to have neither bone-dissolving osteoclasts nor their less-understood precursors, preosteoclasts. Though the inner bones of the mice were abnormal, as expected, the team also found that the outside layers of the bones were thin.
Moreover, the specialized blood vessels needed to transport bone-building supplies were in scarce supply, suggesting overall that osteoclasts and their precursors regulate bone building, not just bone resorption.
The team grew the two cell types separately in the laboratory and collected the liquid around them to test for proteins released by the cells. They found that preosteoclasts—but not mature osteoclasts—secrete a protein called PDGF-BB, a powerful attracter both of cells that make bone-building cells and those that make the specialized blood vessels.
As expected, when the preosteoclasts of mice were prevented from making PDGF-BB, the mice had weak bones.
“Before a new building is constructed, the roads have to be in place so that the materials and equipment can be brought in,” says Cao. “In a similar way, preosteoclasts call blood vessels into an area before bone-building cells begin to make new bone.”
Why the drug works
When mice were given an animal form of odanacatib, the numbers of their preosteoclasts and osteoclasts increased, and they secreted more PDGF-BB. The increased PDGF-BB brought in more cells for making blood vessels and bone, which led to more of the specialized blood vessels and thicker bones.
The drug appears to slow down the maturation of preosteoclasts, Cao says, lengthening the time they secrete PDGF-BB before becoming osteoclasts and restoring the balance between bone resorption and bone rebuilding.
Odanacatib is produced by Merck & Co. Inc. and has already gone through phase III clinical trials with good results, Cao says.
“It is unusual to see a single drug that decreases bone resorption and increases bone rebuilding at the same time,” Cao says. “Beyond that, we now know just how important preosteoclasts and PDGF-BB are to bone building, which is information we can use in designing future studies.”
The National Institute of Diabetes and Digestive and Kidney Disorders, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, China’s National Science Fund for Distinguished Young Scientists, and Merck funded the research.
Source: Johns Hopkins