Objectives. To evaluate the contribution of leptin, an adipose-derived hormone, to the pathophysiology of osteoarthritis (OA), by determining leptin in both synovial fluid and cartilage specimens from human joints, and by investigating the effect on cartilage of intra-articular injection of leptin in rat.

Methods. Leptin levels were measured by enzyme-linked immunosorbent assay (ELISA) in synovial fluids sampled from OA patients undergoing either knee replacement surgery or knee arthroscopy. Besides, histological sections of articular cartilage and osteophytes obtained during surgery for total knee replacement, were graded using the Mankin score, and were immunostained using antibodies to leptin, TGF_ and IGF-1. For experimental studies, various doses of leptin (10, 30, 100 and 300μg) were injected into the rat knee joint. Tibial plateaus were collected and further processed for proteoglycan synthesis by radiolabeled sulfate incorporation, and for expression of leptin, its receptor (Ob-Rb), and growth factors by RT-PCR and immunohistochemistry.

Results. Leptin was found in synovial fluids from human OA-affected joints, and concentrations were correlated to Body Mass Index. A marked expression of the protein was seen in OA cartilage and in osteophytes, while few chondrocytes produced leptin in normal cartilage. Furthermore, the pattern and level of leptin expression were related to the grade of cartilage destruction, and paralleled those of growth factors (IGF-1 and TGFb-1). Animal studies showed that leptin strongly stimulated anabolic functions of chondrocytes, and induced the synthesis of IGF-1 and TGFb-1 in cartilage at both mRNA and protein levels.

Conclusion. These findings provide a new peripheral function to leptin as a key regulator of chondrocytes metabolism, and indicate that leptin may play an important role in the pathophysiology of OA.

Purpose of the study: This study was designed to assess the role of leptin in the development of osteoarthritis (OA) by searching for its presence in the synovial fluid (SF), tissues, and cartilage of osteoarthritic joints in humans and by observing the effect of intra-articular injections of leptin in the rat.

Material and methods: The leptin level in SF was measured (ELISA) in twenty patients (ten female, ten male, mean age 70 years). Presence of leptin, TGF beta and IGF1 in cartilage (and osteophytes) was detected by immunohistochemistry after histological evaluation (Mankin). In the rat, leptin was injected into the knee joint at the dose of 30 and 100 μg. After the immunohistological study, proteoglycan synthesis was assessed (S35 integration) as was the expression of leptin, TGF beta1 and IGF1 using RT-PCR.

Results: This study demonstrated for the first time the presence of leptin in synovial fluid (0.6–17.4 and 5.3–28.4 μg in male and female specimens respectively). There was a significant correlation with body mass index. Leptin was over expressed in chondrocytes of osteoarthritic cartilage and was correlated with the histological score (leptin not detecable in normal cartilage). IGF1 and TGF beta1 were expressed in osteoarthritic chondrocytes. The topographic distribution and the intensity of labeling varied with the histological score. There was a strong expression of TGF beta 1 only in osteophytes. In the rat, leptin stimulated anabolic functions of the chondrocyte: maximal effect at 30 μg (medial tibial plateau) and 100 μg (lateral tibial plateau). Leptin over expressed transcripts IGF 1 and TGF beta 1. This effect was confirmed at the protein level.

Discussion: Leptin is an adipocytokin which regulates food intake and energy expenditure at the hypothalamic level. A mechanical mechanism is the primary explanation of osteoarthritis in weight-bearing joints in obese patients. But leptin is also present specifically in non-weight-bearing joints in obese subjects. A biological factor is thus incriminated which might be leptin produced by adipose tissue. Leptin is overexpresssed in the cartilage of the osteoarthritic knee. This is in favor of a role for leptin in the pathogenesis of OA via synthesis of TGF beta 1 and IGF 1. This effect of leptin could explain the relationship between body mass index and the risk factor for osteoarthritis.