Abstract
IntroductionAdiponectin has been implicated in the pathogenesis of osteoarthritis (OA). We studied the effects of adiponectin on the OA cartilage homeostasis.MethodsImmunohistochemical analysis was performed to evaluate differential expression of adiponectin receptors (AdipoRs) in nonlesional and lesional areas of OA cartilage. Cartilage and chondrocytes from the knee joints of primary OA patients were cultured in the presence of adiponectin (0~30 μg/ml). The levels of total nitric oxide (NO), matrix metalloproteinase (MMP)-1, -3, and -13, and tissue inhibitor of metalloproteinase (TIMP)-1 were measured in the conditioned media. The levels of inducible NO synthase (iNOS) and MMPs were determined with the quantitative real-time reverse transcription-polymerase chain reaction. The concentrations of collagenase-cleaved type II collagen neoepitope (C1-2C) were determined in the supernatant of adiponectin-stimulated OA cartilage explants. The effects of kinase and NOS inhibitors were evaluated in the adiponectin-stimulated chondrocytes.ResultsThe expression levels of both AdipoR1 and AdipoR2 were significantly higher in lesional than in nonlesional areas of OA cartilage. The increased rate of AdipoR1-positive chondrocytes was twice that of AdipoR2-positive chondrocytes when compared between nonlesional and lesional areas. Adiponectin-stimulated OA chondrocytes showed increased total NO and MMP-1, -3, and -13 levels compared with nonstimulated cells. The TIMP-1 level was not affected. The C1-2C levels were increased by adiponectin in OA cartilage explant culture. AMP-activated protein kinase (AMPK) and c-Jun N-terminal kinase (JNK) inhibitors (compound C and SP600125) significantly suppressed adiponectin-induced production of total NO and MMP-1, -3, and -13. Inducible NOS inhibitors enhanced the expression of the adiponectin-induced MMPs.ConclusionsAdiponectin causes matrix degradation in OA cartilage and increases MMPs and iNOS expression via the AMPK and JNK pathways in human OA chondrocytes. The catabolic effects of adiponectin may be counteracted by NO.
Highlights
Adiponectin has been implicated in the pathogenesis of osteoarthritis (OA)
Adiponectin has been considered one of adipokines implicated in OA pathogenesis, based on the following clinical observations: (a) plasma adiponectin levels were significantly higher in OA patients than in healthy controls [8], and (b) higher plasma adiponectin levels were observed in female patients with erosive hand OA than in those with nonerosive OA [9]
Chen et al [12] reported that adiponectin upregulates tissue inhibitor of metalloproteinase (TIMP)-2 and downregulates IL-1b-induced matrix metalloproteinase (MMP)-13 in OA chondrocytes, whereas Lago et al [13] showed that adiponectin induces nitric oxide synthase (NOS), IL-6, MMP-3, MMP-9, and MCP-1 in murine ATDC5 chondrogenic cell lines
Summary
We studied the effects of adiponectin on the OA cartilage homeostasis. Adipose tissue is a highly active endocrine organ that secretes many hormones involved in energy metabolism, inflammation, and immune response. Such hormones, collectively termed adipokines, exhibit cytokine-like actions including anti- and pro-inflammatory effects [7]. Chen et al [12] reported that adiponectin upregulates tissue inhibitor of metalloproteinase (TIMP)-2 and downregulates IL-1b-induced matrix metalloproteinase (MMP)-13 in OA chondrocytes, whereas Lago et al [13] showed that adiponectin induces nitric oxide synthase (NOS), IL-6, MMP-3, MMP-9, and MCP-1 in murine ATDC5 chondrogenic cell lines. Further to elucidate the effect of adiponectin on OA cartilage homeostasis, we investigated adiponectin-induced catabolic activity in OA chondrocytes and matrix degradation of cartilage explant
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