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. Credit: Martin Stolz

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."

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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.