Finding Early Signs of Arthritis

Atomic-force microscopy could advance osteoarthritis drug development.

Osteoarthritis, which affects about 14 million people in the United States alone, occurs when cartilage between joints degrades and disappears, leaving joint bones to grind painfully against each other. Therapies can alleviate some of the pain, and some patients undergo joint replacements, but there is no cure. Now nanotechnologists at the University of Basel, in Switzerland, have demonstrated that the molecular changes characteristic of the disease’s earliest stages can be detected using an atomic-force microscope (AFM). The researchers hope that using the extremely sensitive technique to monitor response to osteoarthritis therapies will speed the development of more-effective drugs for the disease.

Molecular checkup: Atomic-force microscopy images show molecular changes in cartilage decades before symptoms show up. In this image of osteoarthritic cartilage, collagen fibers are lined up instead of randomly ordered, as in healthy cartilage. The white arrows point to a gap in the fibers, and the silvery diamond represents the microscopy probe.

Other research groups have used AFM, one of the standard tools of materials science, to study the mechanical properties of tissues including bone and even individual cells such as cancer cells. The researchers, led by Martin Stolz, a nanotechnologist at the University of Basel, are the first to apply the technique to cartilage. AFM can detect cartilage breakdown decades earlier than can conventional diagnostics, the team reported in Nature Nanotechnology this week.

The symptoms of osteoarthritis are caused by molecular-level changes in the tissue that aren’t visible on conventional diagnostics such as x-ray images. “Osteoarthritis, like many other diseases, starts at the level of molecules, [and current techniques] don’t look at where it starts,” says Stolz. “The molecular scale is where you first have changes–that’s where you should address them.”

Cartilage is made up of tough collagen fibers that provide structure and soft, water-attracting supportive proteins that hold the collagen in position. In osteoarthritis, the supportive proteins in the cartilage disintegrate, drying out the joint and leading to disruption of the collagen fibers and eventual loss of cartilage altogether. Osteoarthritis is conventionally diagnosed with x-ray images or when a doctor, using a minimally invasive surgical probe called an arthroscope, notices changes in the appearance of the cartilage. Normal cartilage looks white and shiny under the arthroscope, but when osteoarthritis is under way and the tissue begins to break down, cartilage loses its shine and takes on a velvety appearance. By the time these changes are visible, Stolz notes, the greatest tissue damage has already happened.

Because AFM probes the mechanical properties of cartilage, not its appearance, it’s much more sensitive, says Hari Reddi, an orthopedist at the University of California, Davis, who was not involved in the research. In the AFM data, the tiny increases in spacing between the collagen fibers and their increasing stiffness–changes characteristic of the early stages of the disease–are visible.

In its study, the team found that AFM could pick up cartilage degradation in healthy mice well before the tissue showed visual signs of aging, and even before an electron microscope–a high-resolution imaging system that doesn’t measure mechanical properties–picked up changes. The team also detected damage in the cartilage of mice with a disease similar to human osteoarthritis when the mice were just one month old–well before the animals showed signs of the illness.

When the researchers used AFM on human-cartilage biopsies taken from patients undergoing knee or hip replacements, they found that it could pinpoint age-dependent breakdown in tissue–even in outwardly perfect cartilage–long before other instruments could. “We’re providing a nanoscale measurement that shows the breakdown of [molecules],” says Stolz. “You cannot detect that by any other means.” It’s possible that the technique could eventually be used to provide minimally invasive, early diagnosis of osteoarthritis. “By the time a patient comes in and complains, it’s too late. The cartilage has gone to pot,” says Reddi.

Even if clinical trials show the value of AFM for diagnosing the disease, Stolz acknowledges, there’s still no cure. However, AFM could help speed the development of osteoarthritis therapies. “If you produce a potential drug, you have to wait six months before you see its effect on the macro scale” using x-ray imaging or an arthroscope, says Stolz. “Our tool clearly showed the changes at one month … If you think about it in the development of drugs, it saves a lot of time and money.” Jingsong Wang, a rheumatologist at the University of Pennsylvania School of Medicine, agrees that the technology’s greatest benefit will be in drug development, noting that nine major osteoarthritis drugs failed in clinical trials due to the fact that patients did not show progress. “You have to show the progression in your treated group using an imaging tool, and the only approved tool is x-ray,” says Wang. “A [more] accurate measuring tool is a first step to studying this.”

The researchers hope to develop an arthroscope that integrates an AFM tip, enabling doctors to more accurately monitor the progression of osteoarthritis, and offering a better tool for assessing the effectiveness of osteoarthritis therapies currently under development. Stolz also plans to use the microscope on blood vessels in the heart and the brain to determine if AFM could detect early signs of risk of heart attack or stroke.

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