Time for a breakthrough
Published on 01 November 2011
Model of an enzyme inhibitor (shown in red) blocking the action of an enzyme (shown in green).
Osteoarthritis research lags behind that into inflammatory forms of arthritis. Research manager Dr Lisa Croucher wonders why, and looks at how our basic laboratory science is shedding light on this complex condition.
Why hasn’t osteoarthritis enjoyed an “anti-TNF revolution” of the kind we have seen for inflammatory arthritis? It could be said that osteoarthritis has suffered an image problem, too easily dismissed as just another consequence of ageing. This mind-set has delayed research that may well have produced drugs of the kind that are now transforming the lives of millions with inflammatory arthritis.
“Catch-up” research in the last few decades has told us that osteoarthritis is every bit as complex as rheumatoid arthritis, but is a very different disease with its own unique set of biological and environmental factors. Scientists and doctors have gained important basic knowledge about how and why so many people develop osteoarthritis, but they have also suffered some discouraging setbacks in their early attempts to develop new drugs.
Arthritis Research UK is determined to improve the lives of those with osteoarthritis by supporting research that aims not just to understand how osteoarthritis starts and develops, but that also reveals new opportunities for the development of more effective drugs.
The scientific “starting point” for this rejuvenated research activity is the one feature that truly defines the disease – destruction of the cartilage. Cartilage is a complex material. It owes its shape, strength and unique shock-absorbing abilities to a tough, three-dimensional meshwork of large protein molecules – the cartilage matrix. In osteoarthritis, the protective structural matrix is gradually broken down, leaving other important cartilage molecules exposed and vulnerable to damage. Despite attempts at self-repair, the cartilage eventually becomes thinner and weaker, unable to withstand the day-to-day traumas of normal use. Scientists reason that if damage to key cartilage molecules can somehow be prevented early on in the disease process, the cartilage can be saved from its almost inevitable track towards destruction and loss.
Large collagen fibres, similar to those that form the ‘scaffold’ of joint cartilage
Understanding enzyme activity in osteoarthritis is key to the development of new drugs
The molecules that are pivotal to this approach are enzymes – “biological scissors” that speed up the breakage of large protein molecules into small pieces. Low-level enzyme activity is important for normal tissue maintenance, but in osteoarthritis, some enzymes are over-produced or are over-active, tipping the balance from healthy cartilage turnover to irreversible destruction. Blocking excessive enzyme activity would seem to be a logical approach to preventing cartilage destruction, and scientists have already attempted this by producing drugs based closely on the body’s own “natural” enzyme inhibitors.
The failure of these early trials taught scientists much about the pitfalls of this kind of drug development. Often, the same enzymes that cause destruction in the cartilage perform vital normal functions elsewhere in the body – blocking them can have unwanted, even toxic effects. In some cases, the new drugs were simply not effective in preventing cartilage destruction. Scientists have worked hard to address the issues that the early trials presented, but finding a safe and effective drug target for osteoarthritis – the “magic bullet” – is still a challenge.
Blocking the activity of destructive enzymes
A recent important breakthrough was the finding that slightly modifying some of these natural inhibitors helps to restrict their activity to cartilage, minimising their side-effects in other parts of the body. Professor Hideaki Nagase and colleagues Dr George Bou-Gharios and Dr Linda Troeberg at the Kennedy Institute of Rheumatology are now exploring the potential of drugs based on one natural enzyme inhibitor, TIMP-3, for new osteoarthritis treatments. Their work in animal models of osteoarthritis shows promise for human disease.
“This is a unique and very exciting finding, and the potential of TIMP-3 based therapy is now also under investigation in the US,” says Professor Nagase. “TIMP-3 alone may be a challenge to use for osteoarthritis therapy as it is not an easy molecule to produce in large quantities. In combination with another drug, Pentosan, we may be able to use much less TIMP-3 to give the same blocking effect.”
Further work is in progress to test the effectiveness of this approach, with any therapy still some years away.
"Developing new, more effective approaches to treating osteoarthritis depends on a thorough understanding of the many environmental and biological factors that interact to cause joint destruction. Knowledge about cartilage destruction in osteoarthritis is progressing fast, and the detailed research carried out by some of Arthritis Research UK's laboratory scientists is taking us closer towards the development of new drugs that aim to slow down or even stop the progression of this devastating disease."
Closing down the enzyme “factory”
Exploring ways to interfere with enzyme production is the focus of Professor Ian Clark’s work at the University of East Anglia. Professor Clark’s Norwich-based team is investigating the power of microRNA molecules – tiny pieces of DNA-like material that interfere with the reading of the DNA “instruction manual.” Early work has demonstrated a strong natural link between the levels of an important cartilage destroying enzyme and the microRNA that controls its production in cartilage cells. Findings such as this provide researchers with the clues they need to develop drugs that build on our body’s own natural processes.
“We have really just scratched the surface of the microRNA story,” says Professor Clark. “There are likely to be many more microRNAs in cartilage, perhaps forming a network to control the production of a range of enzymes implicated in osteoarthritis. We hope that finding ways to manipulate the levels of some cartilage-specific microRNAs may give us some new leads in the search for drugs that might slow or even halt cartilage destruction in osteoarthritis.”
Professor Drew Rowan at Newcastle University is also exploiting new knowledge about how enzymes are produced to identify new drug targets for osteoarthritis. Professor Rowan’s team has found that molecular “signals” produced by inflamed joints can stimulate the production of potent destructive enzymes in cartilage; understanding how these signals are generated and finding ways to weaken or block them altogether is the aim of the team. “This is very basic, but fundamentally important laboratory research,” says Professor Rowan. “If we can gain a thorough understanding of the many molecules involved in the control of enzyme production and how they interact with each other, we can begin to identify the most important molecules to target for the development of new drugs for osteoarthritis.”
Developing new, more effective approaches to treating osteoarthritis depends on a thorough understanding of the many environmental and biological factors that interact to cause joint destruction. Knowledge about cartilage destruction in osteoarthritis is progressing fast, and the detailed research carried out by some of Arthritis Research UK’s laboratory scientists is taking us closer towards the development of new drugs that aim to slow down or even stop the progression of this devastating disease.