Osteoarthritis and the metabolic syndrome: more evidence that the etiology of OA is different in men and women.

Projections by the Centers for Disease Control (CDC) suggest that if current trends continue, by 2030, 20% of the US population will be over age 65, and 86% or the population will be overweight or obese1,2. As our population ages and becomes more obese, prevalence is increasing for diseases related to aging and obesity, such as osteoarthritis (OA) and the metabolic syndrome—a cluster of cardio-metabolic risks secondary to impaired insulin action including hypertension, increased abdominal girth, hypertriglyceridemia, low high density lipoprotein (HDL-cholesterol), and elevated fasting glucose. While both have aging and excess adiposity as important risk factors, OA and the metabolic syndrome have only recently been associated with one another. In the US National Health and Nutrition Examination Survey (NHANES), wave III (1988–1994), with data from over 7,000 adults, each component of the metabolic syndrome was more prevalent in persons with OA3. In the Japanese Research on Osteoarthritis Against Disability (ROAD), the odds of OA increased with the presence of each additional component of the metabolic syndrome4. Similarly, In the Michigan Bone Health and Metabolism Study, in obese women, the presence of two or more cardio-metabolic risk factors was associated with more reports of persistent knee pain over the previous 3 years5. While obesity is a well-recognized risk factor for OA in weight-bearing knee joints6,7, the association of OA with the metabolic syndrome is not completely explained by an obesity-induced increased biomechanical load. Overweight and obese persons also have an increased risk for OA in hands, which are not weight-bearing, implicating systemic factors in the obesity-OA connection8,9. Likely, the systemic connection between OA and the metabolic syndrome revolves around altered metabolism and inflammation. The pathogenesis of OA and the metabolic syndrome each involve abnormalities in common metabolic intermediates including glucose, hormones, several growth factors, transcription factors, nitric oxide and reactive oxygen species10. Further, over the last several decades, both OA and the metabolic syndrome have been increasingly recognized as low-grade inflammatory conditions with elevations in systemic inflammatory markers such as hsCRP11,12. For both entities, there are clear pathogenic roles for inflammatory mediators such as IL1β and TNFα10. Additionally, leptin, a pro-inflammatory hormone produced by macrophages in adipose tissue and a key mediator of the metabolic dysregulation associated with obesity, has been linked to OA pathogenesis10. Leptin is best known for regulating energy intake as an appetite suppressant, but also plays a role in osteoclast and chondrocyte proliferation and collagen synthesis10. In work published in this issue, Karvonen-Gutierrez, Sowers, and Heeringa have contributed new insights to the mechanisms linking OA and the metabolic syndrome. They observe that relations between OA and cardio-metabolic risk factors, including leptin, are present for both genders and in both obese and non-obese individuals. However, their work demonstrates that these relations differ between men and women in both magnitude, and the specific molecules and pathways involved. These authors used data from NHANES III (1988–1994) participants 60 years of age and older who had both fasting blood samples and knee radiographs. Knee radiographs were non-weight bearing so that, while not accounting for joint space narrowing or cartilage degradation, the OA definition primarily reflected the presence of osteophytes. Of the 1,066 participants included in this analysis, 34% had OA, defined as a Kellgren–Lawrence (KL) grade ≥ 2. Not surprisingly, persons with OA had a higher BMI (40% were obese). Similar to Puenpatom and Victor3, glucose, LDL-cholesterol, triglycerides, and blood pressure were significantly higher and HDL-cholesterol was significantly lower in persons with OA than those without. In addition to the earlier report, even after adjustments for covariates, this investigation revealed strong relations for OA with homeostatis model assessment-insulin resistance (HOMA-IR), a surrogate for insulin resistance, and leptin. Most notably, the authors report relations for these cardio-metabolic risk factors and knee OA that were unique for each gender and obesity status. In non-obese men, body mass index (BMI) and HOMA-IR were the risk factors most strongly related to knee OA. In obese men, BMI was not related to knee OA, but HOMA-IR was again the risk factor most strongly related. For both non-obese and obese women, BMI continued to be a strong predictor of knee OA, but in contrast to other strata, HOMA-IR was inversely related to knee OA in obese women. Leptin relations were particularly interesting. For women, there were positive associations such that for obese women an increase of 5 fg/L of leptin contributed a 1.28 increased odds of radiographic knee OA. In contrast, for both non-obese and obese men, leptin levels were inversely related to the presence of radiographic OA. These findings highlight that independent of the effects of obesity, altered metabolism is related to knee OA, but that these relations differ for men and women. While insulin resistance is associated with an increased odds of knee OA in men, increased leptin is associated with increased odds in women, perhaps reflecting the previously observed gender differences in relations between these risk factors and fat deposition. Typically, insulin resistance is more strongly related to visceral adiposity, which is particularly prominent as a cardiovascular risk factor in men, and leptin levels are related to amounts of subcutaneous fat, which tends to be a predominant fat depot for women13. Given the increased prevalence of OA in women, gender differences in associated factors and potential mediators are not too surprising. Gender differences have been noted for OA at epidemiologic, radiographic, circulating biomarker, hormonal, and cellular levels. A gender dimorphism exists for the impact of OA on pain and quality of life such that women report higher levels of pain and greater reductions in quality of life than men14,15. A review of magnetic resonance imaging (MRI) comparisons of men and women highlights variability in findings but concludes that women appear to have lower knee cartilage volume than men16. Despite similar KL grades, as compared to men, women exhibit higher levels of the bone resorption biomarker, serum C-terminal telopeptide of collage type I (CTX-I), and the cartilage degradation biomarker, urine C-terminal telopeptide of collage type II (CTX-II)17. In contrast, men exhibit higher levels of serum hyaluronan (HA), an indicator of synovial inflammation suggesting gender-specific pathogenic mechanisms16. Gender differences in OA have been attributed to differences in sex hormones, as lower levels of estradiol and its catabolic metabolite, urinary 2-hydroxyestrone are associated with the development of knee OA18. Interestingly, both estrogen and testosterone influence chondrocyte progenitor potential but through unique gene expression and regulatory pathways16. Thus, a gender dimorphism clearly exists for OA at multiple levels and as reinforced in the work of these authors. Such differences suggest that OA pathogenesis might proceed via unique gender-specific pathways based on underlying hormonal and anatomic differences. As we seek to better understand the metabolic and inflammatory contributions to OA, it is imperative that we continue to carefully evaluate for potential differences by gender.