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 .
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