Published 9/1/2010
E. Anne Ouellette, MD, MBA; Anna-Lena Makowski, HTL

Sexual dimorphism and osteoarthritis: The role of leptin

The differences between men’s and women’s expression of hereditary osteoarthritis (OA) are now well known. Not only are women more often affected by OA than men, but obese women have a higher risk of OA developing than obese men do. The risk of OA development in obese individuals increases by between 9 percent and 13 percent per kilogram increase in body weight.

Biomechanical factors are the major causes of OA in weight-bearing joints. The joint loading alters site-specific gene expression of cartilage, resulting in the onset of OA. But scientists have also found a link between obesity and OA in the non–weight-bearing joints of the hand. It is possible that leptin—a peptide hormone product of the obesity gene—plays a role in OA development, although the exact mechanism for its involvement is still being researched.

Linking leptin and osteoarthritis
Leptin is a 16-kDa nonglycosylated protein product of the obese gene (ob), manufactured mainly by adipose tissue. Research has found a direct correlation between leptin levels in synovial fluid and body mass index (BMI), with synovial fluid leptin levels in the same range as serum leptin levels. The amount of circulating leptin is directly proportionate to the total amount of fat. Women may have higher levels of leptin than men because of their higher total body fat composition. Women with OA have higher levels of leptin in synovial fluid than men with OA (mean 12.95 mg/L [±8.92 mg/L] in women vs 8.16 mg/L [±5.50 mg/L] in men).

Studies on leptin-deficient obese mice have found no signs of OA in the knee joints, despite the additional weight bearing. Therefore, leptin is most likely involved in other factors associated with OA: inflammation (prostaglandins), bone mass, and cartilage degeneration. Leptin receptors are present on bone marrow stromal cells, osteoblasts, and osteoclasts, which contribute to bone metabolism. Leptin’s effect on osteoblasts may be responsible for osteophyte development in OA-affected joints.

Chondrocytes are also capable of producing leptin. Patients with OA have higher levels of leptin within their chondrocytes than patients without OA. The effects of leptin on cartilage matrix regulation are more complex than those for bone metabolism. At moderate concentrations, locally and/or systemically produced leptin stimulates chondrocyte and osteoblast proliferation to repair damaged cartilage. This repair mechanism is believed to be initiated by leptin’s stimulating anabolic production of insulin-like growth factor 1 (IGF-1) and transforming growth factor beta (TGF-ß). However, animal studies show that excessive and prolonged exposure to these growth factors causes OA damage.

Leptin has also been linked to increased production of catabolic factors (matrix metalloproteinases 2 and 9 and cathepsin D) involved in the progression of OA and the destruction of articular cartilage. Higher levels of leptin, found in women and in obese individuals who may be resistant to its effects (much like resistance to insulin in patients with diabetes), may contribute to the onset of OA.

Research has shown that estrogen has an effect on cartilage and that estrogen is stored in fat. Because both estrogen and leptin levels are related to fat stores and storage, this may explain some of the multifactorial aspects of OA in women. Women are clearly affected more by OA than men, most likely because of women’s higher adipose tissue levels.

Leptin and obesity
Obesity is a primary risk factor for OA, but its role is not clearly understood. Adipose tissue is now considered to be an endocrine organ that actively secretes cytokines and other molecules, including leptin. In addition to regulating chondrocytes, osteoblasts, and osteoclasts, leptin regulates adipose tissue mass and body weight through a negative feedback loop involving the hypothalamus. Mutations in the ob gene or the gene encoding the leptin receptor result in severe obesity.

The relationship between BMI and the risk of OA developing is well established. Similarly, correlations exist among serum leptin concentrations, body fat, and OA development. Yet in leptin-deficient and leptin receptor-deficient mice, morbid obesity was not linked to OA development. Additional studies of leptin signaling, obesity, and OA development are needed to clarify these interrelationships.

Weight loss has been linked to a decreased progression of OA and can be beneficial in patients recovering from joint surgery. But simply telling a patient to lose weight is usually not productive for either the patient or the physician. This is partly because the relationships between hormones and satiety are complex and not completely understood.

Leptin is one of the hormones responsible for the sense of satiety. Patients who are leptin-receptor–resistant do not receive hunger signals or satiety feedback. A team approach to weight loss that combines exercise and nutrition is necessary to help these patients lose weight. The internist’s familiarity with diabetes, obesity, and the correlated system failures that occur with these diseases is also important. This is not just about willpower and self-discipline, but about trying to change or defy the signaling in the body on a permanent basis.

Leptin deficiency is also associated with low total bone mass due to decreased cortical bone formation. Because of this, as the patient loses weight, it is important to support the skeleton with supplements such as Vitamin D and calcium along with exercises that put stress across the bone.

Leptin helps explain the nonmechanical side of OA. It is related to obesity, and serum levels can be modulated by weight gain and/or loss. Future research into a therapeutic target using any of the leptin pathways—such as stimulating repair via anabolic factors or reducing cartilage destruction by inhibiting the catabolic factors—may lead to a novel treatment for OA. Resolving leptin resistance might be another therapeutic pathway to treating OA. The disproportionate effect of OA on women should warrant research on possible sex-specific responses to such treatments.

E. Anne Ouellette, MD, MBA, has served on the AAOS Women’s Health Issues Advisory Board; she is currently in private practice with Anna-Lena Makowski, HTL. Dr. Ouellette can be reached at eouellette@thehandplace.com

Putting sex in your orthopaedic practice
This quarterly column from the AAOS Women’s Health Issues Advisory Board and the Ruth Jackson Orthopaedic Society provides important information for your practice about issues related to sex (determined by our chromosomes) and gender (how we present ourselves as male or female, which can be influenced by environment, families and peers, and social institutions). It is our mission to promote the philosophy that male and female patients experience and react to musculoskeletal conditions differently; when it comes to patient care, surgeons should not have a one-size-fits-all mentality.