Bethesda, MD- Using naturally-occurring mutant mice with a defective collagen gene, scientists at Harvard have identified a signaling molecule involved in one of the most common causes of disability among the elderly in the United States, osteoarthritis. Inhibitors of this molecule's signaling may eventually be used to slow down the progression of the disease, thus helping to relieve chronic pain in a large segment of the population.
The research appears as the "Paper of the Week" in the January 7 issue of the Journal of Biological Chemistry, an American Society for Biochemistry and Molecular Biology journal.
It is estimated that all individuals over the age of 75 are afflicted with osteoarthritis. The disease, which is actually a group of overlapping but distinct diseases with similar clinical outcomes, is most common form of arthritis. It is characterized by the breakdown of cartilage, which cushions the ends of bones, in the joints of the knees, hips, feet and back. This cartilage breakdown causes the bones to rub against each other, resulting in pain and loss of movement.
"The earliest indication of the disease is a gradual loss of large molecules called proteoglycans from the surface of the joint cartilage," notes Dr. Yefu Li of the Harvard School of Dental Medicine. "This results in a decrease in the mechanical strength of cartilage. At the same time, cells proliferate and form clusters. Then cracks in the cartilage gradually develop and the cracks are filled with a fibrous tissue; this is considered to be the result of unsuccessful attempts by the cartilage cells to repair the cracks. Finally, bony structures, called osteophytes, are formed at the periphery of the joint. The end result is loss of joint function."
Although the causes of osteoarthritis are diverse, mutations in two types of collagens, type IX and XI, have been linked to early-onset osteoarthritis. However, the link between the collagen mutations and the pathogenesis of osteoarthritis is not clear.
To further elucidate the relationship between collagen mutations and the pathogenesis of osteoarthritis, Dr. Yefu Li and his colleagues at Harvard studied mice with a mutation in type XI collagen. These mice exhibit age-related osteoarthritis–like changes in various joints, which is similar to what is seen in humans.
"Information about molecular and cellular events during the initiation and progression of osteoarthritis is limited since current research efforts are mostly focused on either risk factors for the disease or biochemical events in cartilages of joints at later stages of the disease," explains Dr. Li. "However, the similar clinical outcomes in different forms of osteoarthritis suggest that a common molecular sequence of events is responsible for the progression of the disease. Identification of molecules that are critical in this sequence may not only help us to understand the disease better, but may also provide information for the design of new therapeutic strategies for the treatment of osteoarthritis."
Dr. Li and his colleagues found that the mutant mice had increased amounts of the protein discoidin domain receptor 2 (DDR2) in the articular cartilage chondrocytes (cartilage cells) of their knee joints. "DDR2 is a signaling receptor on cell surfaces that binds to collagen fibrils outside the cells," explains Dr. Li. "The normal function of DDR2 is largely unknown. One report demonstrates that the lack of DDR2 results in dwarfism in mice, probably due to decreased proliferation of cartilage cells during bone growth."
The increase in DDR2 caused an increase in the expression of matrix metalloproteinase-13 (MMP-13), a protein that remodels the extracellular matrix by degrading major matrix components.
"Our study suggests that collagen binds to DDR2 and stimulates the production of an enzyme, MMP-13, that in turn degrades the cartilage," concludes Dr. Li. "Our study also identifies a signaling pathway in cartilage cells used by DDR2 to regulate the synthesis of MMP-13. Our results bring us one step closer to identifying a possible early and common step in the development of different forms of osteoarthritis."
Dr. Li's results suggest that inhibitors of DDR2 signaling may be useful as drugs to slow down osteoarthritis progression. This comes as good news in the wake of several drugs used to treat arthritic pain being linked to severe side effects.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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