"We found that the very critical interaction between collagen II and another collagen, collagen IX, is altered as a result of this particular mutation," he says. "The study showed that mutant collagen II is not able to form normal assemblies with collagen IX. The results indicate that mutations in collagen II cause alterations not only on the molecules that carry the mutation but, also, dramatically affect the behavior of normal proteins that function as their natural biological partners.
"We think because this precise framework of cartilage is severely altered, it can significantly contribute to the progression of osteoarthritis." The work, he says, "significantly extends the existing knowledge of how mutations in collagen genes are translated to disease."
Dr. Fertala and his co-workers report their results in December in the journal Biochemistry.
Collagens are structural proteins that provide structural strength to connective tissue, such as skin, bone and cartilage. Collagen II, together with the protein collagen IX, form a "biological alloy." This "alloy" is molded into a fibril-like structure and is arranged in a precise network, providing cartilage with great mechanical strength.
Researchers have previously shown that alterations in the gene for collagen II could contribute to the development of the disease. Other scientists, in fact, had found that some individuals with an early onset and severe form of osteoarthritis harbor mutations that change an amino acid sequence in collagen II. But it wasn't clear why this led to osteoarthritis. In the study, Dr. Fertala and his group followed the formation of the cartilage scaffolding and watched how the mutation in collagen II and the resulting amino acid change in the protein altered the precise alignment of the two types of collagens.
According to Dr. Fertala, the results will help to identify "weak points" in the complex cartilage structure in patients with a mutated collagen gene and protein.
He was surprised by the findings. "The problem with understanding how these mutations work is that in many cases, a collagen mutation results in a protein still behaving normally. But when you study the interaction with its normal partner, it shows something has gone awry. This is very new in the collagen research field.
"The next step with this model would be to try to somehow block the mutated sites to prevent these unspecific interactions, which results in osteoarthritis," he notes. Finding ways to counteract such weak points in the cartilage structure might slow down or reduce the development of the disease.
Osteoarthritis is a very common and disabling disease of cartilage of the joints that affects millions of people worldwide. It is the most common cause of disability, absence to work and places an enormous socioeconomic burden. Its cause is unknown, but a number of factors such as aging, mechanical stress, inflammation and trauma are often associated with its development.
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Phyllis Fisher
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Journal
Biochemistry