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Dr. Monte Hunter is chair of the MCG Department of Orthopaedic Surgery and a coauthor of the study in the journal Scientific Reports. Dr. Sadanand Fulzele is a bone biologist in the Department of Orthopaedic Surgery at the Medical College of Georgia at Augusta University. Photo: Phil Jones/Medical College of Georgia

We’ve known for years that women are almost 10 times more likely to injure their anterior cruciate ligament (ACL) than men. While research has suggested different reasons for this, one of the most compelling studies came out of Johns Hopkins last year—experiments performed on mice indicated it is testosterone that allows the male ACL to withstand more force than the female ACL.

“Our thought was that while estrogen may make the female ACL weaker and more prone to injury, the male hormone testosterone may act to strengthen the ACL and protect it from injury,” said study author William Romani at the time.

Now, a new, unrelated study from the Medical College of Georgia on the fluid that helps protect knee cartilage also suggests estrogen is to blame—in this case, for a woman’s increased chances of developing osteoarthritis.

Researchers and study authors Sadanand Fulzele and Monte Hunter investigated the “messages” microRNA cells in synovial fluid were sending out in males and females with and without osteoarthritis. To do so, they looked inside the fluid to exosomes.  All cells excrete exosomes as a way to communicate. The exosomes carry things like protein, lipids and microRNA, which can impact the expression and actions of different genes.

"What we found [between males and females] is there was no change in the number of exosomes, but a change in the microRNA cargo they carry," Fulzele says.

In other words, in females, the microRNA was carrying messages it wasn’t supposed to, as opposed to carrying the correct messages of joint health in males.

When looking at the exosomes in synovial fluid, the researchers found in males that 69 microRNAs were significantly downregulated and 45 were upregulated. In females, however, there were 91 downregulated versus 53 upregulated. In total, females had more than 70 biological processes altered compared with males who had closer to 50.

Females’ microRNA was supposed to be sending signals promoting estrogen signaling and collagen-producing cells—but this was either turned off or altered. That resulted in lower estrogen levels, which is proven to prompt the production of cells that destroy bone, ultimately resulting in net bone loss.

Therefore, the researchers suspect that estrogen plays an important role in determining which microRNAs the exosomes contain.

While osteoarthritis is usually the result of normal wear and tear, there are additional factors, including genetics, injury, obesity, overuse and being a female.

“Wear and tear that comes with aging, and can be accelerated and aggravated by injury, can inflame the membrane, which may alter the cargo in the exosomes and the messages they carry,” Fulzele says.

Fulzele and Hunter are already exploring ways to block the microRNAs that are causing cartilage destruction. But in the future, in a step toward personalized medicine, Hunter said he and his colleagues hope to examine exosomes in the synovial fluid for indicators of a patient's specific instigators of cartilage destruction. If they are successful, the team can then work on the development of a cocktail—potentially a mix of microRNA inhibitors and joint health-promoting microRNAs—that can be injected into the knee to target and help resolve the debilitating destruction.

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