Is leptin the link between obesity and osteoarthritis?
© The Author(s) 2004
Published: 13 September 2004
Leptin is a small, 16-kDa protein produced and secreted primarily by adipocytes found in white adipose tissue. Initially discovered as a central regulator of appetite and energy expenditure, leptin may also be involved in the regulation of metabolic activity in the growth plate and bone. Since obese individuals have an increased incidence of osteoarthritis (OA), we evaluated the contribution of leptin to cartilage changes associated with this degenerative disease.
Leptin levels in synovial fluid samples obtained from OA patients undergoing joint replacement were measured by ELISA assay. In addition, histologic sections of tibial plateau cartilage and osteophytes obtained from OA patients were graded using the Mankin score, and were immunostained using antibodies to leptin, transforming growth factor beta 1 (TGF-β1), and insulin-like growth factor 1 (IGF-1). For experimental studies, various doses of leptin (10, 30,100, and 300 μg) were injected into the knee joints of rats. Tibial plateaus were collected and processed for proteoglycan synthesis by radiolabeled sulfate incorporation, and for expression of leptin and growth factors by RT-PCR and immunohistochemical analysis.
Our results indicated that leptin was observed in synovial fluid from the human OA-affected knee (n = 14 men, 8.16 ± 5.5 μg/l; and n = 6 women, 12.95 ± 8.92 μg/l). These leptin concentrations were correlated with the body mass index (r = 0.572, P < 0.01). Interestingly, a marked expression of leptin was observed in OA cartilage, especially in fibrillated cartilage with clusters 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 TGF-β1). When injected into rat knee joints, leptin stimulated chondrocytes anabolic functions and induced the synthesis of IGF-1 and TGF-β1 in cartilage at both mRNA and protein levels.
Taken together, these findings provide a new peripheral function to leptin as a key regulator of chondrocyte metabolism, and indicate that leptin may play an important role in the pathophysiology of OA.
This study was supported by grants from the Contrat de Programme de Recherche Clinique, CHU Nancy, France.