Synopsis: New research from Shriners Hospitals for Children Canada and McGill University Montreal shows how bone cells repair themselves, giving important clues as to how to improve future care.
Researchers from Shriners Hospitals for Children® - Canada, affiliated with McGill University, have discovered that bone cells experience injuries and rapidly repair themselves after all kinds of mechanical stresses - from pressure placed on bones during simple walking, to extreme forces experienced during intense exercise. The teams' first study was published this fall in the open-access journal eLife and their follow-up study, that confirms their conclusions and makes further discoveries, has just been published in the November edition of the Journal of Cell Science.
"Our first research project shows that bone cells adapt to physical forces, such as encountered during exercise, and that the more the bone cells suffer from micro-injuries, the more quickly they repair themselves," explains senior author Svetlana Komarova, PhD, from Shriners Hospitals for Children - Canada's Research Centre and Associate Professor at McGill University. This research, which includes discoveries that challenge the current thinking on the matter, will potentially help patients with a variety of bone issues, including many children and teens treated at Shriners Hospitals for Children. The study may also provide a scientific basis for new treatments for many elderly people with bone degeneration and even astronauts, who also suffer from bone loss after experiencing micro-gravity in space.
"The research shows how adaptive our bodies really are," says Dr. Komarova. "The body has its own regulatory system - even for minor bone repair. If we better understand how that works, we can eventually reduce our dependency on drugs to repair any damage." The research, while still at a fundamental stage, will not only allow scientists and clinical specialists to understand what types of exercises could help their patients with bone diseases, but also when, how often and for how long exercises should be performed. It could, therefore, help clinicians more specifically prescribe certain exercise or movement regimens to patients with bone issues.
Gravitational and muscle forces act on the skeleton during any physical activity resulting in a complex combination of forces, strains and pressures that can break down bone cells. Bone cells translate these mechanical stresses into a complex chain of molecular events that allow bones to adapt and repair. Increases in cell levels of calcium and the release of an important molecule called adenosine triphosphate (ATP), considered by biologists to be the energy fuel of life, are known to be early events following mechanical stress of bone cells, but exactly how mechanical forces lead to ATP release remained unresolved.
"The goal of our study was to examine the exact mechanism of how bone cells adapt and repair themselves after mechanical stimulation. To do that, we needed to study ATP release, what caused it and what was its consequence," explains lead author Nicholas Mikolajewicz, PhD student at McGill University and Shriners Hospitals for Children - Canada.
"It had previously been proposed that ATP comes from vesicles - tiny membrane sacs within the cell," continues Mr. Mikolajewicz. "We were surprised to find, following ATP release using fluorescent dyes, that the greater the number of vesicles released, the less ATP was released. This proved that previous assumptions were incorrect."
The team concluded that mechanical stress on bone cells causes ATP to be released through micro-injuries in the cell membrane. They found that an influx of calcium, which in turn switches on a molecule called protein kinase C (PKC), controls vesicles that repair the membrane of the bone cell, stopping the leakage of - and therefore preserving - ATP. "We also established that the more that bone cells are subjected to this repair mechanism, the more rapidly the repair took place," concludes Dr. Komarova.
In the second phase of their research, Dr. Komarova and colleagues, including lead author Nicholas Mikolajewicz, set out to perform a meta-analysis of all studies done to date on mechanically stimulated ATP release. For this large statistical analysis, about 250 papers published on the topic were analysed. The researchers looked at their approach to ATP release measurements in order to establish the consensus.
The research team discovered that when mechanical forces are applied to mammalian cells (animal or human cells), about 24 million molecules of ATP are released from each cell, quantifying the molecular release for the first time. Interestingly, they found that when different types of forces (pressures, strains) were applied to the cells, ATP was released through different routes. Importantly, their analysis revealed that ATP release acts differently in people depending on their disease state. They found that mechanically-stimulated ATP release is higher in people showing inflammation and injury, but it is lower in people with hereditary and metabolic conditions, such as cystic fibrosis and type II diabetes.
"We also found that ATP release upon mechanical stimulation does not only happen within bones, but within nearly every cell of the body," explains Dr. Komarova. This discovery will therefore have an impact on other medical research studies of mechanically-stimulated ATP release in different cell types.
Shriners Hospitals for Children is a health care system with locations in the U.S., Canada and Mexico. Our staff is dedicated to improving the lives of children by providing pediatric specialty care, conducting innovative research, and offering outstanding teaching programs for medical professionals. Shriners Hospitals for Children - Canada is the only Canadian establishment within the Shriners hospitals for Children network. This bilingual, short-term, acute care hospital provides ultra-specialized orthopaedic care to children from coast to coast in Canada, the U.S. and around the world. The mission of the hospital is to promote health and provide treatment and rehabilitation to infants, children and young adults with orthopaedic and neuromuscular problems such as scoliosis, osteogenesis imperfecta (brittle bone disease), club feet, hip dysplasia, leg length discrepancies and cerebral palsy. The hospital is committed to excellence and innovation in clinical practice, research and education and to ensuring patients and their families are treated in a caring, family-friendly environment. Affiliated with McGill University, the hospital provides clinical experience and teaching for residents and allied healthcare professionals.
The paper 'Mechanically-stimulated ATP release from murine bone cells is regulated by a balance of injury and repair' can be freely accessed online at https://doi.org/10.7554/eLife.37812 Contents, including text, figures and data, are free to reuse under a CC BY 4.0 license.
The paper 'Mechanically stimulated ATP release from mammalian cells: systematic review and meta-analysis' can be accessed via the Journal of Cell Science at http://jcs.biologists.org/lookup/doi/10.1242/jcs.223354
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