DALLAS – Researchers have long known there are sex disparities when it comes to the prevalence and severity of knee osteoarthritis, a disease that causes cartilage degeneration. Now, investigations underway at UT Southwestern Medical Center point to biological differences in the knee cartilage of male and female animals that could explain substantial variances in rates of osteoarthritis between the sexes and may eventually lead to tailored treatments that take these into account.
Paula Hernandez, Ph.D
“If we really want to improve women’s health in orthopedics, we have to understand how men and women are different at the tissue, cellular, and molecular level,” said Paula Hernandez, Ph.D., Instructor of Orthopaedic Surgery at UTSW, and Biomedical Engineering at UTSW, who leads research on structural, cellular, and mechanobiological aspects of sexual dimorphism in cartilage. “This is a start toward identifying those differences.”
Articular cartilage acts as a cushion in our joints, allowing for frictionless movement, and its degeneration can be painful and debilitating. Several tissues within the knee joint including cartilage, meniscus, and ligaments work in balance to provide mechanical stability to the knee. Women are more susceptible than men to injuries of the anterior cruciate ligament (ACL), a key to knee stability, and that damage can result in a mechanical imbalance exposing cartilage to injurious friction and excessive mechanical load, triggering degeneration.
Because many women experience joint problems after menopause, Dr. Hernandez explained, the prevailing hypothesis has been that hormonal changes accompanying this life stage were responsible for differences with men. However, she and her colleagues wondered whether the factors that could contribute to joint issues were present far earlier.
To answer this question, Dr. Hernandez and her team worked with cartilage from the knees of cows between 24 and 30 months old – equivalent to humans 18 to 20 years old. This material is very similar to human cartilage but far easier to acquire from animal models than human patients, she said.
The study, published in Cartilage, found that knee cartilage isolated from male and female animals differed significantly in mechanical properties, microstructure, and gene expression long before hormonal changes from menopause.
Articular cartilage is formed by a load-bearing extracellular matrix (ECM) rich in collagen and proteoglycans with sparsely embedded chondrocyte cells. The thin pericellular matrix (PCM) that surrounds each chondrocyte acts as a mechanical connector between chondrocytes and the ECM. Findings from this study revealed a sex-specific abundance of some ECM and PCM proteins that could help explain sex differences in cartilage mechanical properties.
Mechanical tests revealed that bovine cartilage from the males was more than three times stiffer than that from females. When the researchers examined the protein content of this cartilage, they found significant differences in the content of specific protein types in tissue from the male and female animals. Treating individual chondrocytes – the cells that produce cartilage – with an inflammatory chemical changed the activity in different sets of genes between the sexes.
Dr. Hernandez said these findings show striking differences in cartilage between the males and females relatively early in life – long before the end of these animals’ reproductive period. Her team is continuing to investigate when these differences first appear and whether they’re tied to chromosomal sex, sex hormones, or another cause.
“By better understanding the root cause of sex differences and embracing them,” Dr. Hernandez said, “we can get closer to closing the gap in knee osteoarthritis between the sexes.”
UT Southwestern was named a High Performing Hospital for orthopedic care in 2022-23 by U.S. News & World Report, placing it in the top 10% of all hospitals in the U.S.
Other UTSW researchers who contributed to this study are faculty members Chao Xing, Ph.D., Professor, Eugene McDermott Center for Human Growth, Tre Welch, Ph.D., Assistant Professor, Cardiovascular and Thoracic Surgery, Yasin Dhaher, Ph.D., Professor, Physical Medicine & Rehabilitation, and Jamie Wright, Ph.D., Assistant Instructor, Cardiovascular and Thoracic Surgery; computational biologist Adwait A. Sathe, Ph.D.; research associate Zahra Barati, M.S.; and Conner Hutcherson, a student in the Graduate School of Biomedical Sciences. Dr. Dhaher holds the R. Wofford Cain Distinguished Chair in Bone and Joint Disease Research at UTSW.
This study was funded by the Department of Orthopaedic Surgery at UT Southwestern.
About UT Southwestern Medical Center
UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 24 members of the National Academy of Sciences, 18 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,900 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 100,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 4 million outpatient visits a year.