Biological factors in early life may ‘play a major role’ in osteoarthritis sex disparities
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Chromosomal, hormonal and structural differences between the bodies of girls and boys may explain why osteoarthritis incidence is elevated in women vs. men later in life, according to a review published in Osteoarthritis & Cartilage.
In their article, Paula A. Hernandez, PhD, instructor and principal investigator in the department of orthopedic surgery and the department of biomedical engineering at the University of Texas Southwestern Medical Center, and colleagues, noted that previous research has shown a “sex-specific component” to OA.
“OA is a slow disease. It takes many years to detect and diagnose, as the damage in cartilage and the joint often progresses slowly,” Hernandez told Healio. “If we take this into consideration, only looking at menopausal age means we are delaying the action for preventive and reparative approaches.
“We wondered whether we are overlooking important differences between male and female bodies early in life that could affect the outcome of joint degeneration later in life,” she added. “We realized that there are significant sex differences in knee anatomy, tissue structure and biomechanics that could be related to a higher risk for knee injuries and OA.”
To examine the factors that may contribute to higher OA risk among women compared with men, Hernandez and colleagues compiled clinical data for multiple tissues within the knee joint, including tissue from the articular cartilage, meniscus and anterior cruciate ligament. The researchers additionally assessed sex-specific differences in human anatomy, physical activity and metabolic signatures to determine how these factors may impact disease severity and incidence in women later in life.
Healio sat down with Hernandez to discuss the history of research showing elevated OA incidence among women and how changes in the activity levels of girls and young women may contribute to their higher risk.
Healio: Why did you choose to study sex-specific differences in the knee joint? Were there other signs that there is a higher incidence and severity of knee OA in women later in life prior to your study?
Hernandez: There is substantial evidence that OA is more common in women after menopause, thanks to the effort of many scientists and physicians around the world. That was the foundation of our article, as we compile part of this evidence and propose that several biological factors — anatomy, physiological, metabolic, biomechanical — present early in life which could be playing a major role in the disparities observed in OA later in life.
The knee joint, together with hand joints, show the most sex differences in terms of incidence and severity in OA. Although we are interested in both, we started with the knee as it is a load-bearing joint needed in many sports and physical activities.
Nowadays, more and more young women are participating in activities that were previously male dominated, such as certain competitive sports and military training. However, there is still a lack of understanding of strategies to prevent the development of OA in women later in life, especially after suffering knee injuries such as ACL tears, meniscal tears, or cartilage lesions.
Healio: Apart from these youth sports injuries, why did you investigate factors such as knee anatomy, biology and metabolic factors?
Hernandez: We were looking for evidence of sex differences much earlier than postmenopausal age, which is when OA is mostly detected. OA is a slow disease. It takes many years to detect and diagnose, as the damage in cartilage and the joint often progresses slowly. If we take this into consideration, only looking at menopausal age means we are delaying the action for preventive and reparative approaches. We wondered whether we are overlooking important differences between male and female bodies early in life that could affect the outcome of joint degeneration later in life.
We realized that there are significant sex differences in knee anatomy, tissue structure and biomechanics that could be related to a higher risk for knee injuries and OA. Metabolism is another important factor, as this is the way that the body takes energy and transforms it into usable building material.
In our article, we show the evidence and propose a hypothesis based on that evidence, but we still need to continue our research to ultimately prove that those factors are behind the sex disparities in OA. Here is where basic and translational sciences are most needed.
Healio: In the study, you observed differences between boys and girls in articular cartilage, meniscus and ACL arise before puberty that cannot be explained solely by sex hormones. Why is that?
Hernandez: This is an interesting topic, as we may assume that sex hormones are the main drivers of the sex disparities, and they probably are. However, males and females differ in a whole chromosome — XX versus XY. Even though in female placental mammals, one of those X chromosomes is subjected to X chromosome inactivation (XCI) to prevent having a double dose of the same chromosome, sometimes it occurs that certain genes escape the inactivation.
The chromosomal effect in OA is still under-studied, but it is quite interesting that sex differences in the knee are observed even before the onset of pubescence — that is, before the influence of sex hormones.
Healio: What are the distinct roles of hormones and chromosomes on OA risk?
Hernandez: As mentioned before, studies specifically investigating the chromosomal role in OA risks are lacking compared with those studying sex hormones. The lack of estrogen in menopausal women appears to be crucial in enhancing cartilage degeneration, as some evidence indicate that estrogen has a protective role in certain tissues of the joint.
Interestingly, the onset of pubescence leads to other changes that also affect tissues in the joint, neuromuscular control and joint biomechanics. A new factor that is emerging, but that may involve a crosstalk between sex hormones and chromosomes, as well as their individual contributions, is the effect of epigenetic changes. These are biochemical modifications or “flags” in the DNA, without altering its sequence, that control whether the expression of a gene is on or off.
Several factors affect these modifications, including behavioral — diet, physical activity, smoking, etc. — and environmental, but most interestingly, the epigenome is also affected by sex hormones as well as the same mechanisms involved in the X chromosome inactivation in females.
Research is still needed to unveil the role of epigenetics in OA. However, promising recent studies are revealing that epigenetic changes are more common and more relevant in OA than previously thought. This topic was, however, outside the scope of our article.
Healio: You also observed variation between males and females in the abundance of amino acids and other metabolites. What does this mean for OA development?
Hernandez: Metabolism can indicate how effective our bodies are in building, remodeling, or repairing tissue, and in a number of other physiological events. Having differential metabolomic profiles in OA samples suggests that males and females may have differential pathophysiological mechanisms, and/or differential progression of the disease. More studies are needed, but this could help guide more tailored treatments considering, for example, diet, exercise and the response to inflammation.
Healio: Is there a social component between boys and girls that impacts lifestyle and, subsequently, OA onset later in life?
Hernandez: It has been shown that physical activity influences cartilage volume. The tissues in the knee benefit from physical activity — bone, muscle, tendons, ligaments, meniscus — and this can be beneficial for the future.
Boys are, in general, more active than girls, but even after adjusting for physical activity, boys have a larger cartilage volume compared with girls. If there are intrinsic differences that influence tissue homeostasis, perhaps we should focus on exposing girls to more physical activity at physiological levels. Not necessarily participating in competitive sports, but developing routines of physical education designed to strengthen muscles and reduce tissue laxity in girls.
Healio: There is a section of the study titled: “What can we learn from transgender individuals?” What are some of the things we can learn?
Hernandez: Transgender individuals who go through gender-affirming therapies are exposed to levels of sex hormones that are higher or lower than what their bodies naturally produce. Tissues are influenced by sex hormones, but the underlying molecular mechanisms happening on a female cell in response to high levels of testosterone, or a male cell exposed to high levels of estradiol, are still poorly known and understood. Of note, many studies investigating the role of estradiol have used male cells and assume that female cells will behave similarly, which is not correct.
Once again, research in transgender musculoskeletal health is unfortunately under-studied. We urgently need to understand how the musculoskeletal system changes during and after undergoing gender-affirming hormone therapy, so we can properly evaluate what their risks are for injuries or development of OA.
Some of the few studies focusing on this area are already showing that transgender individuals are at risk for osteoporosis. As we learn how their bodies change, and consider additional factors such as physical activity, muscle mass, fat tissue, vitamin D and inclusion of aromatase in their hormonal therapy, physicians can properly manage their health needs during their gender transition and pay special attention to reducing their risks for OA and musculoskeletal diseases.
Healio: What can pediatricians and pediatric rheumatologists learn from these findings that could help them manage patients in the clinic?
Hernandez: As a basic scientist, I can only say that we should not assume that a treatment designed for a male will work on a female. Instead, the approach selected by the physician should be tailored to each sex and gender. Preventive measures could comprise sex-specific physical routines or therapies considering their intrinsic or extrinsic sex hormones, in case of a different gender.
Healio: Similarly, how can your findings help adult rheumatologists provide optimal care?
Hernandez: Same as before, we should not assume that a treatment designed for males will work on females. Although still under investigation, the underlying processes in OA might be a bit different between males and females. Considering their differences in metabolism, pain perception, inflammation, recovery from injuries, etc., an option is that physicians consider whether a female patient already went through menopause or not, if they had pregnancies, if they are active, or what is their diet.
Women are often disregarded by physicians in many diseases — not only the musculoskeletal ones. Unfortunately, most of the current knowledge has been obtained by studying only males or combining both males and females. Female-specific data have been historically avoided due to the unfounded fear of their intrinsic variability. Nowadays, thanks to collective effort of scientists, physicians, and funding agencies that require the inclusion of male and female data, the truth about women’s health is starting to emerge.
In summary, science and medicine should start working together to find elemental differences in order to design tailored treatments based on sex and gender.
References:
Hernandez PA, et al. Osteoarthritis & Cartilage. 2024;doi:10.1016/j.joca.2024.04.015.
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