Evidence for a key role of leptin in osteoarthritis

Abstract

Objective. To evaluate the contribution of leptin (an adipose tissue-derived hormone) to the pathophysiology of osteoarthritis (OA), by determining the level of leptin in both synovial fluid (SF) and cartilage specimens obtained from human joints. We also investigated the effect of leptin on cartilage, using intraarticular injections of leptin in rats.Methods. Leptin levels in SF samples obtained from OA patients undergoing either knee replacement surgery or knee arthroscopy were measured by enzymelinked immunosorbent assay. In addition, histologic 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, transforming growth factor ␤ (TGF␤), and insulin-like growth factor 1 (IGF-1). For experimental studies, various doses of leptin (10, 30, 100, and 300 g) 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, its receptor (ObRb), and growth factors by reverse transcriptasepolymerase chain reaction and immunohistochemical analysis.Results. Leptin was observed in SF obtained from human OA-affected joints, and leptin concentrations correlated with the body mass index. Marked expression of the protein was observed in OA cartilage and in osteophytes, while in normal cartilage, few chondrocytes produced leptin. 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␤1). Animal studies showed that leptin strongly stimulated anabolic functions of chondrocytes and induced the synthesis of IGF-1 and TGF␤1 in cartilage at both the messenger RNA and the protein levels.Conclusion. These findings suggest a new peripheral function of leptin as a key regulator of chondrocyte metabolism, and indicate that leptin may play an important role in the pathophysiology of OA.

The role of adipocytokines in the pathogenesis of knee joint osteoarthritis

“…Adipocytokines acting in an autocrine or paracrine manner stimulate chondrocytes in a dual way. One of the first studies on the impact of leptin on cartilage cells revealed that this peptide increases the anabolic activity of chondrocytes by inducing IGF-1 and TGF-β expression at both mRNA and protein levels [55]. However, further studies have shown contradictory results.…”

Targeting subchondral bone for treating osteoarthritis: what is the evidence?

“…The localised effect of TGF-β and IGF-1 may be linked to an abnormal response to leptin by OA subchondral bone osteoblasts. This may occur as the expression of leptin stimulates TGF-β and IGF-1 in joint tissues [73].…”

Obesity and osteoarthritis: Is leptin the link?

“…Otero and colleagues showed that costimulation of chondrocytes with leptin and IL-1 or interferon increased the expression of inducible nitric oxide synthase and increased nitric oxide production, thus mediating down-regulation of matrix synthesis and up-regulation of MMP activity (20). In contrast, leptin has anabolic effects in cartilage in that it stimulates 2 growth factors, transforming growth factor ␤ and insulin-like growth factor 1 (21). Thus, in cartilage, the question is whether leptin is pro-degenerative or prorepair.…”