New genomic map identifies hundreds of genes governing bone health

In a global discovery published in Genetics of Natureresearchers successfully mapped the cells and genes that regulate bone formation and loss on an unprecedented scale and discovered the critical role that blood vessel cells play in bone health.

By combining the genomic sequence with data from half a million individuals, the research team identified hundreds of previously unknown genes that govern bone health and revealed cells that line blood vessels as one of the drivers of bone repair – a role that had not been appreciated until now.

Led by Professor Peter Croucher and Dr Ryan Chai from the Garvan Institute of Medical Research, Associate Professor John Kemp from Mater Research and Professor Graham Williams and Professor Duncan Bassett from Imperial College London, the team’s findings fundamentally advance our understanding of skeletal disease.

It is hoped the discovery will enable the development of new treatments to rebuild lost bone – offering hope to nearly half of people 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 the bones.

“Most people don’t realize that bones are constantly changing – the human body replaces its skeleton every 10 years or so,” said Professor Croucher.

This is an extremely important process, but until now we have had very limited understanding of the cells and mechanisms that control this bone turnover. Most of the drugs now available focus only on arresting the bone disease, rather than rebuilding the lost bone, which is really important in reversing the damage.”

Peter Croucher, Professor, Garvan Institute

The most detailed map of the cells and genes that regulate bone health

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

Dr Chai said the team’s extensive 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 been shown before to play a role in maintaining bone health, which is an important finding,” added Dr Tsai.

Surprising new role for blood vessel cells

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

Associate Professor Kemp said that by analyzing genetic and bone mineral density data from half a million people who participated in the UK Biobank, the team were able to pinpoint exactly which cells drive the skeletal disease.

“These include cells known to regulate bone formation and bone loss, as well as blood vessel cells that, until now, have had an underappreciated role in bone health,” added Associate Professor Kemp.

Resources to accelerate the development of new treatments

Professor Croucher said the research revealed new therapeutic opportunities not only against bone disease, but also cancer.

“Bone is the main hiding place for dormant cancer cells and a common site of recurrence, so identifying the cells and genes that drive bone metabolism also opens up new opportunities to prevent cancer metastasis,” he said.

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

“We hope that sharing this knowledge can speed up the development of new treatments that prevent diseases such as osteoporosis and reverse the damage caused by them,” said Associate Professor Kemp.