Synovial Fluid Holds Clues to Why Knee OA Is More Common in Females

    Researchers at the Medical College of Georgia at Augusta University have found evidence that in synovial fluid, the messages that cells are sending and receiving via microRNA are different in males and females – which may affect the ability of the fluid to protect the cartilage in the knee joints.

    This difference may help explain why knee osteoarthritis (OA) – which affects more than 30 million Americans – is more common in women than in men and may point toward a more targeted way to diagnose and treat OA, said Sadanand Fulzele, PhD, a bone biologist in the MCG Department of Orthopaedic Surgery.

    The study by Dr. Fulzele and his colleagues has been published by the journal Scientific Reports.

    Changes in microRNA in Exosomes

    Synovial fluid is known to provide clues about joint health, so MCG researchers decided to look at what messages cells in the region were sending and receiving by examining exosomes in the fluid.

    “What we found is there is no change in the number of exosomes, but a change in the microRNA cargo they carry,” Dr. Fulzele said.

    Dr. Fulzele and his colleagues isolated the mostly round exosomes in discarded human synovial fluid from patients with and without OA. In male patients, 69 microRNAs were significantly downregulated and 45 were upregulated. In female patients, there were 91 downregulated versus 53 upregulated microRNAs.

    This seems to have a more significant impact in females than in males: In total, more than 70 biological processes were altered in females, compared closer to 50 in males, the researchers said.

    Estrogen May Be the Key

    Dr. Fulzele and his colleagues suspect that the gender differences found in exosome content helps explain gender differences in disease incidence, and they believe estrogen is key to the differences.

    Particularly in females with knee OA, they found microRNA that should have been sending messages that are good for the joints, such as promoting estrogen signaling and collagen-producing cells, had been turned off or were otherwise altered.

    Lower estrogen levels, such as in menopause, prompt production of more cells that destroy bone. In this environment, those bone-consuming cells also tend to live longer, which can result in a net bone loss. Reduced risk of OA is considered a benefit or hormone replacement therapy.

    The MCG researchers hypothesized that estrogen plays an important role in determining which microRNAs the exosomes contain. In fact, when they used aromatase inhibitors to reduce the availability of estrogen, they found that a small lineup of microRNAs decreased in number.

    When they treated cartilage cells from healthy females with exosomes from males and females with OA, significantly fewer healthy cartilage cells lived after exposure to the exosomes from patients with disease. Expression of genes that make the extracellular matrix that is the framework of cartilage decreased, while expression of genes that promote inflammation increased.

    The researchers only found 1 microRNA, MiR-504-3p upregulated in both male and female osteoarthritis patients. Although it’s unclear what MiR-504-3p does, Dr. Fulzele thinks it degenerates cartilage, which is the crux of OA. In future studies, he and his colleagues will use MIR-504-3p inhibitors to remove it from the equation and try to determine the function of this tiny piece of RNA.

    Looking for Specific Instigators of Cartilage Destruction

    All cells excrete exosomes as a way of communicating. They carry cargo, such as protein, lipids, and microRNA, which can impact the expression and actions of many different genes.

    In the case of the synovial fluid, the exosome source is likely cells in the synovial membrane that lines the joints and produces the fluid, Dr. Fulzele said. 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.

    Knee replacement becomes the endgame for patients whose dwindling cartilage can literally translate to one bone rubbing against another.

    D. Monte Hunter, MD, chair of the MCG Department of Orthopaedic Surgery and a co-author of the study, hopes that soon he and his colleagues will be able to examine exosomes in synovial fluid of the knee for indicators of specific instigators of cartilage destruction.

    They then hope to devise a cocktail – potentially a mix of microRNA inhibitors and mimics of joint health-promoting microRNA delivered in manmade exosomes – that can be injected into the knee to target and help resolve the debilitating destruction.

    MCG researchers are already exploring ways to block the microRNAs that are causing destruction.


    Kohle R, Hunter M, Jadeja RN, et al. Gender-specific differential expression of exosomal miRNA in synovial fluid of patients with osteoarthritis. Sci Rep. 2017 May 17;7(1):2029. doi: 10.1038/s41598-017-01905-y.