BUILD IT UP, TEAR IT DOWN - TRYING TO STOP OSTEOPOROSIS

Build it up, tear it down.

In cities across the world the same scene has been playing out for decades. 

Building goes up...building comes down; new replaces old, stylish replaces ugly.

And it maintains some sort of equilibrium; there aren’t too many being built or too many being demolished. 

But what if this equilibrium swung wildly the other way and buildings started being demolished all around us, our cities wrought with wastelands and empty space?

This is what plays out in our bones when we suffer from osteoporosis. 

In bones, the construction crews are cells called osteoblasts – they make bone. 

The demolition crews are called osteoclasts – and they take bone (a process called resorption). 

In healthy individuals this dance of bone creation and demolition moves along like our city scapes, being slowly but surely torn down and replaced with something new. 

In fact, up to 10 per cent of our bone mass is undergoing remodelling at any given time. 

But when we suffer from osteoporosis, our osteoclasts are removing much more bone material than our osteoblasts are building – making our bones fragile and weak.

And it’s a common problem. 

According to the Australian Bureau of Statistics there were over 500 000 Australians suffering from osteoporosis in 2005. 

And the most recent figures show taxpayers fork out over $221 million of annual health spending as a result. 

As a condition that predominantly affects the elderly, the cost of treating osteoporosis is only going to increase as Australia’s population ages.

So what can we do about it? 

Associate Professor Gary Schenk and his team from the University of Queensland’s School of Chemical and Molecular Bioscience have just published research that may offer a lead.

An enzymologist himself, Associate Professor Schenk and his team work on an enzyme called purple acid phosphatase.

“Purple acid phosphatase is the target for the development of drugs against osteoporosis,” he said.

“In patients that suffer from osteoporosis this enzyme is overly active, so the aim is to inhibit it.”

It is known that purple acid phosphatase is involved in bone resorption – the removal of bone material – and its activity is hence associated with osteoporosis.

Studies with genetically modified mice have shown that those animals that make too much purple acid phosphatase develop osteoporosis, while those that make too little of the enzyme exhibit the opposite condition (osteopetrosis – where bones become too dense). 

“We now have made a series of compounds that are able to bind tightly to the enzyme and stop it from working,” Associate Professor Schenk said. “These compounds are the most potent inhibitors that have been reported so far.”

“The idea is to make a compound that binds really well to the enzyme in a way that it will stop the enzyme from working.”

The research is conducted in collaboration with Drs Ross McGeary, a synthetic chemist, and Luke Guddat, both also residing in the School of Chemistry and Molecular Biosciences.

“Ross makes these compounds, and Luke and I test how they interact with the enzyme,” said Associate Professor Schenk.

It’s the finding of these compounds that is difficult, or more aptly, the finding of compounds that work well enough.

“There are two approaches we take.  One is based on structure; basically we have a strategic plan, we look at the structure, design a molecule, make it and then see how it binds to the enzyme – a rational but slow process.

“The other approach is to use a library of thousands of random compounds and test them all, hoping to identify one or the other that happens to bind to the enzyme and stop it from working – a “shotgun” approach.

“So we do both…and just see which one works.”

The jury is still out on how, specifically, the action of purple acid phosphatase leads to the onset of osteoporosis.

“People who suffer from osteoporosis clearly have significantly increased levels of purple acid phosphatase, and this enzyme is a major marker to diagnose the disease” Associate Professor Schenk said, “but how exactly it contributes to bone resorption is still subject to debate.”

One suggestion is that purple acid phosphatase removes a phosphate from some other proteins in the bone, thus interfering with the release of the osteoclasts (the bone-removing cells) – essentially the osteoclasts are stuck and keep removing bone.

“We do not really know how it biologically contributes…we only know that it does,” Associate Professor Schenk said.

Despite the promising results, Dr Schenk said the research still had a number of years to go before any drug could come on the market, although they received a new Australian Research Council grant last November to continue their work.

“Ahh well drug design…that cycles. I mean we are now basically entering the second cycle and our aim is to eventually identify molecules that bind even better than the ones we have, but still have drug like properties and are safe for use in humans.”