For years, physiologists looking closely at bones noticed something puzzling. It was a microscopic prison break, blood cells slipping unseen from the enclosed depths of the bone marrow into the general circulation.
“We have the bone marrow, which produces the blood cells, and when you need them, you need them urgently. But how do they get out?” said Svetlana Komarova, who studies bone biology at McGill University in Montreal.
Sure, textbooks showed entrances and exits, but they were enormous arteries and veins at the ends of bones — an impractical route if the body needs a quick burst of the cells forged within our marrow. But in a paper published Monday in Nature Metabolism, a team of German immunologists announced they’d found a whole network of tunnels that explain the escape. While their first observations were in mice, they found a similar map of secret capillaries in humans, too, which may shed light on how certain drugs work.
“I have never seen such vessels,” said Ralph Müller, who studies bone biomechanics at the Swiss Federal Institute of Technology in Zurich, and who was not affiliated with this study. “But we have never really looked either. So this is a surprise for me … that certainly will need some replication in other labs.”
That anatomy should still contain such surprises is itself something of a surprise. It’s easy to think that 19th-century anatomists pulled apart the body tendon by tendon, vein by vein, describing and drawing every filament they came across, no matter how tiny. But eight years ago, Matthias Gunzer, an immunologist at the University Duisburg-Essen, in Germany, saw something that didn’t fit the current models. He had dyed some white blood cells red and green so that he could trace the path of their fluorescence through a mouse’s leg under the microscope. What he saw was strange: These cells seemed to be crossing a wall of solid bone.
He figured that someone else would have described the channels they were taking — but as he leafed through the mouse blood-vessel literature, he found no mention of them. He decided he would have to describe them himself. “In order to be convincing,” he said, “you have to show that they are there, demonstrate that there is a blood-filled thing.”
To do that, Gunzer’s team treated the bone with a liquid that made it clear as glass, revealing the soft capillaries inside, like insects caught in amber. But that wasn’t good enough; they still needed to prove what it is these tunnels were doing. So they stained proteins that are present in blood vessels and then used a laser to make them light up. Sure enough, in cross section after cross section of a mouse’s tibia, they saw soft, blood-carrying tissue snaking through the bony architecture. And when they used yet another imaging technique — this one allowing them to reconstruct, in 3D, the cave-like world inside a mouse bone — they could see that the very skeleton had hollowed-out canals so that these capillaries could carry blood through.
If these canals wound through the bones of humans, too, Gunzer reasoned, then they should start pricking out blood during surgeries. He isn’t himself a doctor, so he went to see an orthopedic surgeon friend. “I said, ‘Hey, when you look at a naked human bone, do you see punctate bleeding?’ He said, ‘Yes, of course, we see it all the time. For us that’s a sign that the bone is still alive.’”
When they got tiny samples of human bone and used the same chemical to make it transparent, they noticed there weren’t quite as many of the capillaries as there were in the mice, but it looked like they were there.
That might help explain how immune cells could flood so quickly into the bloodstream — but it also has other implications. The channels in the bone through which these capillaries pass are gouged by osteoclasts, cells that naturally degrade bone so that our skeletons can remake themselves. When the researchers gave mice a common class of drugs often prescribed for osteoporosis, the fact that these drugs stopped osteoclasts in their tracks also meant that they couldn’t form new paths for capillaries. In other words, the drugs might increase bone density, but might lessen blood flow between the marrow and the exterior of the bone.
“It’s fantastic,” Komarova said of the potential for better understanding the workings — and side effects — of commonly prescribed drugs.
While Gunzer is excited about the possible applications of the research, part of the thrill was simply stumbling on something new when he thought everything had already been thoroughly explored and mapped. “At the time, I was absolutely not an expert in bone; that helps you see things with entirely innocent eyes, and that might allow you to see things that other people haven’t,” he said. “A lot of people are investigating bones, and none of them have seen these channels, maybe because they’ve been too long in the business.”