Why do women have more trouble after knee injuries? Model explains estrogen’s role

A computer model of the cellular environment inside the knee developed by UT Southwestern Medical Center researchers sheds light on why women tend to have worse outcomes after knee injuries than men. Their findings, published in Scientific Reports, could facilitate research into new therapies for knee inflammatory disorders and personalized treatments for patients with these conditions.

“It’s important when we design any medical intervention that we account for the physiological differences between men and women,” said Yasin Dhaher, Ph.D., Professor of Physical Medicine & Rehabilitation and Investigator in the Peter O’Donnell Jr. Brain Institute at UT Southwestern.

“This study introduces the first biologically informed and inspired mathematical model of synovial joint inflammation that incorporates endocrine sex differences, advancing precision-targeted therapies.”

Dr. Dhaher co-led the study with Conner Hutcherson, Ph.D., a former graduate student at UTSW. Dr. Hutcherson is now a fellow at the Oak Ridge Institute for Science and Education supporting the Biomedical Advanced Research and Development Authority in the U.S. Department of Health and Human Services (HHS).

Post-traumatic osteoarthritis (PTOA), which develops after significant joint injury and often affects the knee, is a leading cause of disability. Not only are women more likely to sustain knee injuries, they are also more likely to develop PTOA.

Researchers have long speculated that sex differences in knee anatomy might be responsible for these disparities. However, Dr. Hutcherson said, few studies have focused on how hormonal differences between the sexes—including changes that occur during the menstrual cycle—might influence outcomes after knee injuries.

Gathering data directly from human patients is problematic because collecting tissue and fluid samples from inside the knee is overly invasive, Dr. Dhaher explained. Yet, the few existing computer models of knee injuries haven’t incorporated sex-specific effects, including the effects of hormones, he said.

To fill this gap, Drs. Dhaher and Hutcherson and their colleagues built on a computer model originally reported in 2018 by Dr. Dhaher and fellow researchers while he was at Northwestern University. The new model examined how three cell types respond to various concentrations of estrogen, progesterone, and testosterone—the three main sex hormones—after a simulated knee injury. Those cell types are chondrocytes, which form cartilage; synovial fibroblasts, which form the lining that surrounds the knee joint; and macrophages, the prevailing type of immune cell found within the knee.

The researchers gathered data to construct the new model from a study at UTSW on hormonal changes during the menstrual cycle in female human subjects, along with previously published studies that examined how cells respond to inflammatory proteins and sex hormones.

The new model suggested that when estrogen concentrations are highest during menstruation—typically just before ovulation—cells in a knee that underwent a simulated injury produced more pro-inflammatory proteins and enzymes that degrade knee tissue, while also producing fewer anti-inflammatory proteins.

Conversely, elevated testosterone levels, characteristic of the hormone environment inside male knees, led to reduced production of pro-inflammatory proteins and degradative enzymes, while increasing production of anti-inflammatory proteins.

Of all cell types and molecules examined in the model, macrophages that invade the knee after injury and the proteins they produce influenced the inflammatory process the most, Dr. Hutcherson said—suggesting therapies aimed at these agents could have the most impact in preventing or treating PTOA.

The study authors suggest their model could eventually be used to study how drugs influence inflammation in simulated male and female knees. They added that doctors in the future could use a similar system to develop personalized therapies for PTOA and other conditions, incorporating a patient’s specific biological characteristics.