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An international team of scientists report that they have successfully mapped the cells and genes that regulate bone formation and loss and discovered the critical role that blood vessel cells play in bone health. By combining genomic sequencing with data from half a million individuals, the research team identified hundreds of previously unknown genes that govern bone health and revealed cells surrounding blood vessels as one of the drivers of bone repair.

The study “Multiscale analysis and functional validation of the cellular and genetic determinants of skeletal disease” is published in Nature Genetics. The team says its findings fundamentally enhance our understanding of skeletal disease. It is hoped the discovery will enable the development of new therapies to rebuild lost bone, offering hope to almost half of all individuals over 50 living with rare and common skeletal conditions such as osteoporosis, osteoarthritis and osteogenesis imperfecta, as well as those with rare bone disorders and cancers that spread to bone.

“Most people don’t realize that bones are constantly changing; the human body replaces its skeleton every 10 years or so,” said Peter Croucher, PhD, professor at the Garvan Institute of Medical Research in Australia. “This is a hugely important process, but until now we’ve had a limited understanding of the cells and mechanisms that control this turnover of bone. “Most of the drugs now available focus only on halting bone disease, rather than rebuilding lost bone, which is really important for reversing damage.”

Detailed map of cells and genes that regulate bone health

The team used single-cell RNA sequencing to measure which genes are switched on within individual cells found in bone, focusing on the interface between the hard bone and bone marrow which is the key site for the formation and breakdown of bone.

The Institute’s Ryan Chai, PhD, pointed out that the team’s analysis found 34 different groups of cells and defined the genes that are active in each of these cell types. “To our surprise, more than half of the genes identified have never before been shown to play a role in maintaining bone health, which is a significant finding,” he added.

The team used its map to identify cells involved in rare and common skeletal diseases, including osteogenesis imperfecta and osteoporosis. For the latter, the researchers analyzed the UK Biobank, one of the world’s biggest and most comprehensive collections of biological samples.

By analyzing genetic and bone density data from half a million people participating in the UK Biobank, the team was able to pinpoint exactly which cells drive skeletal disease, according to John Kemp, PhD, associate professor from Mater Research.

“These include cells known to regulate bone formation and bone loss, as well as blood vessel cells that, until now, have had underappreciated roles in bone health,” he said.

Croucher explained that the research uncovered new therapeutic opportunities against not only bone disease, but also cancer. “Bone is the main hiding place for dormant cancer cells and a common site of relapse, so identifying the cells and genes that drive bone turnover also opens new opportunities to prevent cancer metastasis,” he said.

The team is now further investigating the roles of newly discovered bone-regulating cells and genes in the hope of developing new medicines against these targets. Its data has been made accessible to medical researchers worldwide through an open access platform.

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