Not only are women more often affected by osteoarthritis (OA) than men, but obese women especially have a high risk of developing OA. The risk of OA development in obese individuals increases by between 9 and 13 percent per kilogram increase in body weight.

Biomechanical factors are the major causes of OA in weight-bearing joints. However, scientists have 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 joint fluid and body mass index (BMI), with joint 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 joint 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).

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-B). 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.

Leptin and obesity

Obesity is a primary risk factor for OA, but its role is not clearly understood. Adipose tissue is 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.

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, 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.

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 non-mechanical 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.
Cicuttini, FM., Baker, JR., Spector, TD. The Association of Obesity with Osteoarthritis of the Hand and Knee in Women: a Twin Study. J Rheumatol 1996;23(7):1221-6

Dumond, H., Presle N., Terlain B., Mainard D., Loeuille D., Netter, P., Pottie, P. Evidence for a Key Role of Leptin in Osteoarthitis. Arthritis Rheum 2003;48(11):3118-29.

Van Beuningen, HM., Glansbeck HL., van der Kraan PM., van den Berg, WB. Osteoarthritis-like Changes in the Murine Knee Joint Resulting from Intra-articular Transforming Growth Factor- Injections. Osteoarth Cartilage 2000;8:25-33

Hulth, A., Johnell, O., Miyazono, K., Lindberg, L., Heinegard, D.,Heldin, CH. Effect of Transforming Growth Factor- and Platelet Derived Growth Factor-BB on Articular Cartilage in Rats. J Orthopaed Res 1996;14:547-53

Teichtahl, AJ., Wluka, AE., Proietto, J., Cicuttini, FM. Obesity and Female Sex, Risk Factors for Knee Osteoarthritis That May Be Attributable to Systemic or Local Biosynthesis and its Cellular Effects. Med Hypothesis, 2005;65(2):312-15.

Bao, J-p., Chen W-p., Feng, J., Hu, P-f., Shi, Z-l, Wu, L-d. Leptin Plays a Catabolic Role on Articular Cartilage. Mol Biol Rep, Published online: 10/30/2009 Springer Science+Business Media B.Z. 2009

Griffen, T.M., Huebner, J.L., Kraus, V.B., Guilak, F. Extreme Obesity Due to Impaired Leptin Signaling in Mice Does Not Cause Knee Osteoarthritis. Arthritis & Rheumatism, 2009;60(10):2935-44

Sandell, L.J. (Editorial) Obesity and Osteoarthritis: Is Leptin the Link? Arthritis & Rheumatism, 2009;60(10):2858-60