Even if it is usually accepted that mechanical loading contributes to joint cartilage destruction in overweight patients, recent advances in the physiology of adipose tissue add further insights in understanding the relationship between obesity and osteoarthritis. Indeed, the positive association between overweight or obesity and osteoarthritis is observed not only for knee joints but also for non‐weight bearing joints, such as hands.
5 Furthermore, if weight loss may prevent the onset of osteoarthritis, the loss of body fat is more closely related to symptomatic benefit than is the loss of body weight.
6 These patterns of joint involvement suggest that joint damage may be caused by systemic factors such as adipose factors, so called adipokines, which may provide a metabolic link between obesity and osteoarthritis. Today, adipose tissue, traditionally viewed as a passive store of energy, is considered to be a real endocrine organ that releases a large number of factors, including cytokines, such as interleukin 1 and tumour necrosis factor α, as well as adipokines, such as leptin, adiponectin, resistin, visfatin, and so on, and new ones that are yet to be discovered. These adipokines exhibit pleiotropic functions mediated through both central and peripheral systems, including haemostasis, lipid and glucose metabolism, reproductive functions, blood pressure regulation, insulin sensitivity, bone formation and angiogenesis.
7 So, recent data strengthen the hypothesis that osteoarthritis is a systemic disorder in which dysregulation of lipid homeostasis can be one of the pathophysiological mechanisms leading to osteoarthritis.
8Recent studies provide evidence for a key role of leptin in cartilage homoeostasis. Leptin and its functional receptor have been identified in human chondrocytes and trigger intracellular signal transduction through the activation of STATs 1 and 5, but not STAT 3.
9 Leptin may have important biological effects in chondrocytes, on both growth factor synthesis and anabolism, and also on catabolism. Leptin expression is strongly upregulated in various articular tissues that undergo strong structural and biochemical changes during osteoarthritis—for example, cartilage, osteophytes and subchondral bone—when compared with normal tissues.
10,11 Interestingly, the pattern and level of leptin expression are related to the grade of cartilage destruction, and parallel those of growth factors (insulin‐like growth factor I and transforming growth factor β‐1). The intra‐articular injection of leptin into the rat knee joint has a stimulatory effect on proteoglycan synthesis and is associated with increased expression of insulin‐like growth factor I and TGFβ‐1. In addition to mature cartilage, leptin is also produced in resting and prehypertrophic chondrocytes in the growth plate of mice.
12 In cultured human chondrocytes, leptin increases both the proliferation and the extracellular matrix synthesis, but in a biphasic manner, with a reduced stimulating effect at the highest concentrations. Leptin may thus have a beneficial effect on cartilage synthesis either directly or through the upregulation of growth factors. However, an excess of leptin may account for decreased extracellular matrix synthesis and may lead to lesions similar to those found in osteoarthritis with a high intra‐articular level of growth factors.
13 The increased expression of leptin in markedly damaged cartilage suggests that leptin may trigger cartilage destruction, especially when associated with some local factors. The adipokine synergises with proinflammatory cytokines, such as interleukin 1, to increase nitric oxide production, which is known to interfere with chondrocytes function resulting, in the loss of cartilage matrix through induction of apoptosis, activation of metalloproteinases, and inhibition of proteoglycan and type II collagen synthesis.
14Little is known about the contribution of adiponectin and resistin in osteoarthritis‐affected joints. Available data related to the potential effects of these adipokines in joint disorders indicated that they may have an active role in the pathogenesis of chronic inflammatory joint diseases such as rheumatoid arthritis.
15,16 The inducing effect of adiponectin on metalloproteinase 1 expression in synovial fibroblasts from patients with osteoarthritis suggests that this adipokine may also be associated with key pathways of cartilage matrix degradation.
15In patients with osteoarthritis, leptin, adiponectin and resistin are detected in both the synovial fluid and in the plasma.
17,18 The adipokines exhibit different patterns of distribution between the joint and the circulating compartment: plasma levels of resistin and adiponectin exceed those in the paired synovial fluid, whereas leptin concentrations in synovial fluid are higher than their plasma counterparts.
18 As was found in plasma from obese people when compared with normal subjects, the leptin to adiponectin ratio was shown to be higher in the synovial fluid of patients with osteoarthritis than in plasma. The resulting imbalance between two adipokines known to have opposite biological effects in various diseases such as diabetes or inflammation may contribute to the initiation and/or progression of osteoarthritis. Interestingly, this high level of leptin is associated with a decline in the soluble leptin receptor level, leading to a large rise in free leptin in synovial fluid, the presumed biologically active form of this adipokine. Moreover, a larger amount of free leptin is found in the synovial fluid from female patients with osteoarthritis than in that from male patients, and may explain why obesity and female sex are both risk factors for the development of osteoarthritis.
To date, no clear mechanism could explain the changes in the adipokine levels in the synovial fluid compared with plasma. Various tissues obtained from human osteoarthritis‐affected joints release leptin and adiponectin. Among these tissues, the synovium and infrapatellar fat pad produce the highest amounts of adipokines.
18 Until recently, the fat pad, which is an extrasynovial but an intra‐articular tissue, had been neglected. However, this adipose tissue is able to release growth factors, cytokines and adipokines.
19 Cross talk between the adipocytes and other cells located in the fat pad (macrophages), or in its vicinity (synoviocytes), may also regulate the production of various factors in the joint. Interestingly, osteophytes, which are osteocartilaginous metaplastic tissues, represent the major source of leptin but not of adiponectin. Altogether, these findings indicate that further investigations on the effect of the infrapatellar fat pad and its derived adipokines on chondrocyte metabolism would be helpful to better understand the pathogenesis of (knee) osteoarthritis.
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