The US space agency NASA has awarded a US$750 000 grant to conduct research into how bone weakening in the absence of mechanical loading, as in zero gravity, can be reduced.
Dr Meghan E McGee-Lawrence, biomedical engineer in the Department of Cellular Biology and Anatomy at the Medical College of Georgia, the recipient of the grant, will use the money to better understand how bone loss occurs in space from lack of gravity and also from disuse here on Earth.
“It’s a problem for the astronauts who are on the International Space Station for long periods of time, and it’s going to continue to be a problem for eventually trying to send astronauts to Mars,” Dr McGee-Lawrence said. It is also a problem in patients with spinal cord injuries, undergoing prolonged bedrest or physical inactivity.
“If we can find a way to make bone more sensitive to mechanical loading, then we would be able to increase bone mass with less effort. That is a long-term goal,” she says.
Her focus is the natural sensors of mechanical loading on the bone called osteocytes, and her lab found that tears, called plasma membrane disruptions, occur in osteocytes from mechanical loading, resulting in repair. They showed that these disruptions from loads happen in under a minute, and set off changes like letting in extra calcium, influencing osteoblast and osteoclast activity. If there are few tears from mechanical loading, osteoblasts are not needed and so osteoclasts will resorb some bone matrix. Even walking around has been shown to cause plasma membrane disruptions, something not possible for bedrest patients or astronauts in space.
With this in mind she posed the question, “can we do anything to reverse those processes. Can we do something to the osteocytes to make them either more likely to experience tears or more likely to repair those tears and then, accordingly, make it so there is less bone loss during disuse.”
Fewer tears seem to be not good, and she and her team want to further investigate what happens to the repair rate with disuse. They also want to know the best healing rate; slow for better osteocyte survival, or does osteocyte survival enable faster repair?
“The good news is we can dial it in either direction,” she says. However, they believe faster repair is not better because the calcium influx is linked to the cell’s response.
“Think of a membrane disruption as a doorway into the cell. If you slam the door too quickly, then there is not enough time for the cell to sense that tear and initiate the signaling to respond,” she explained.
She believes that proteins involved in repairing membrane tears, like PRKD1, are logical targets for genetic and pharmacological methods to either increase tears or speed up repair.
“The ultimate goal is can we come up with a way, whether it’s a drug therapy or a different type of regimen that can make these processes work better in astronauts and people on earth who are subjected to disuse as well,” she said.
Even with resistive exercises, astronauts lose bone mass in space. Bisphosphonates are only really effective with age-related bone loss and not loss from inactivity or lack of gravity. With the current most advanced exercise device on the International Space Station, astronauts come back to Earth fitter than when they left but still lose some bone mass. On a three-year voyage to Mars, many astronauts could return with osteoporosis. “That is really a problem. Not only are they losing bone actively while they are in space, at some point they have to come back to gravity… and then what happens?” she says. Recovering bone strength on Earth is a long and difficult process for astronauts. She and her research team are also finding that osteocytes are less likely to repair and survive tears after a long period of disuse.
There are effective therapies, like bisphosphonates, that can help age-related bone loss, but they have not been shown to be effective when disuse is the primary driver. “That is why we need to come up with better targets, more effective targets, to try to prevent disuse-induced bone loss,” she said. While it has long been clear that mechanical load also translates to stronger bones, just how remains a question, she says. She suspects the plasma membrane tears are key.
“We think the formation of these tears is important for how the bone cells know they are being exposed to that level of loading,” she said, with high-impact loading from running and jumping being particularly important. “Cells need a way to know what is going on outside their cell membrane. This is one way to do that.”