New genomic map identifies hundreds of genes governing bone health

In a global breakthrough published in Nature Genetics, researchers have successfully mapped the cells and genes that regulate bone formation and loss at an unprecedented scale 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 – a role that has been underappreciated 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 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 realise that bones are constantly changing – the human body replaces its skeleton every 10 years or so," Professor Croucher said.

This is a hugely important process, but until now we've had a very 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."

Peter Croucher, Professor, Garvan Institute

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

The team used state-of-the-art 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.

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 before been shown to play a role in maintaining bone health, which is a significant finding," Dr Chai added.

Surprising new role for blood vessel cells

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

Associate Professor Kemp said by analysing 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.

"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," Associate Professor Kemp added.

Resource to accelerate the development of new therapies

Professor Croucher said 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 ground-breaking data has been made accessible to medical researchers worldwide through an open access platform.

"We hope that sharing this knowledge can speed up development of new therapies that prevent diseases like osteoporosis and reverse the damage caused by them," Associate Professor Kemp said.