Feel it in your bone cells

Bones, it turns out, are rather like brains: their cells signal to each other to tell them when to grow. This could be good news for osteoporos is sufferers, writes Simon Hadlington

As anyone who has broken one knows, bones are not just passive items that hold up the rest of the body. They clearly have some form of internal signalling system, which helps them mend from breaks. Now an international team of scientists has made an unexpected discovery about that system which could lead to a new generation of drugs for treating bone diseases such as osteoporosis.

Osteoporosis - which causes bones to become weaker - affects around 3 million people in the UK and costs the NHS about pounds 750m a year. Forty people die each year because of osteoporosis-related bone fractures; post-menopausal women are particularly at risk.

The researchers, led by Professor Tim Skerry at the University of York and Dr Larry Suva at Harvard Medical School, have found that bone cells contain signalling apparatus previously thought only to occur in the brain.

The discovery could enable us to eavesdrop on the chemical conversations between bone cells that dictate whether the body's needs demand that bones should - at the cell level - be built up or torn down. Hormonal changes during menopause are thought to interfere with this signalling, causing bone to be degraded unnecessarily.

Bone is being continuously formed and re-absorbed by the body. Whether there is a net loss or gain depends on circumstances. A bone that is stressed, through exercise for example, will gain mass; an unused one loses it. A tennis player's serving arm has greater bone mass than the non-serving arm. Astronauts, whose bones are hardly loaded at all, lose skeletal mass during a space mission. A Finnish study in Friday's Lancet showed that doing three classes of step aerobics a week increased bone mass by up to 3.7 per cent.

"Loading has the greatest effect on stimulating bone formation," says Professor Skerry. "We want to understand the biochemical mechanisms underlying that response."

Bone is a highly complex material that leaves structural engineers feeling envious. It is a composite, consisting of fibres of a tough protein, collagen, embedded in a mineral called hydroxyapatite. This gives it both tensile and compressive strength. It is also a "smart" material. Entombed within the collagen/hydroxyapatite matrix are cells called osteocytes, each of which has scores of thread-like protrusions, forming a network throughout the bone.

Osteocytes act as sensors. When the bone is loaded they send signals to cells at the bone surface, osteoblasts, which instruct them to synthesise new bone. If bone is idle, a third type of cell is called into action. These are osteoclasts, which are manufactured in bone marrow. They "scavenge" excess bone, causing bone mass to decline. It is the unregulated action of osteoclasts that is responsible for osteoporosis.

Professor Skerry and Dr Suva want to know how osteocytes translate a mechanical stimulus - or absence of one - into a chemical message that tells the osteoblasts and osteoclasts what to do.

It is known that bone cells respond very quickly to loading: enzymes in osteoclasts are switched on within minutes of a brief burst of vigorous exercise. One reason for these biochemical changes may be that when osteocytes detect mechanical loading, genes are switched on or off, causing signalling systems to be activated or deactivated.

To test this, the team took two bone samples: one that had been subjected to loading, and an equivalent sample that had not. They then extracted the genetic material from the bone cells and subjected it to a complex procedure to compare which genes were active in the two samples.

There were subtle but clear differences. In particular, one gene which was active in the unloaded sample was absent in the cells from bones that had been loaded. After analysing the DNA sequence of this gene and consulting a database of known gene sequences, Professor Skerry and Dr Suva realised that they had stumbled upon something remarkable.

The gene that was deactivated by loading assembles a protein called a glutamate transporter. Glutamate is an amino acid involved in the transmission of signals between nerve cells. To facilitate its action a particular piece of cellular apparatus is needed, a transporter. This was identified in the brain around four years ago by American researchers, who then screened just about every other tissue in the body for the presence of the transporter - and didn't find it. They thus assumed that it was exclusive to nerve cells. But they did not screen bone.

Having confirmed that the transporter protein was indeed present, Professor Skerry and Dr Suva also identified the other main component of the glutamate signalling system, glutamate receptors.

"It would be very surprising if these molecules were present unless glutamate is involved in signalling between bone cells," says Professor Skerry.

This could be significant in two ways. "If the response to mechanical loading works by glutamate-mediated signalling, drugs which affect glutamate may be able to alter the signalling system. It might be possible to fool the cells into thinking that the bone is being loaded when it is not," he says.

"It also opens a whole new door for the control of bone cells generally, because no-one had thought of glutamate in the context of bone cells before. It is probably involved in things other than the response to mechanical loading."

Professor Skerry's lab in York, which is funded by Smith and Nephew, the Arthritis and Rheumatism Council, the Wellcome Trust, the Nuffield Foundation and the BBSRC (a government research council), has now embarked on the slow process of finding out precisely what role glutamate plays in the biochemistry of bone cells.

He is cautious when asked how soon useful therapies might emerge from the research. "These findings are very new. But because we can tap into the huge expertise on glutamate receptors in the brain we might see treatments in a shorter time than is usual when a new discovery is made."

One thing, however, has become clear. Osteocytes, with their thread-like projections, have long been thought to resemble astrocytes - cells found in the brain. The possibility that glutamate plays an important role in the function of both these types of cell highlights another similarity. The term "bonehead" might not be such an insult after all.

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