Dataset Information

Secreted ?-Klotho maintains cartilage tissue homeostasis by repressing NOS2 and ZIP8-MMP13 catabolic axis.

ABSTRACT: Progressive loss of tissue homeostasis is a hallmark of numerous age-related pathologies, including osteoarthritis (OA). Accumulation of senescent chondrocytes in joints contributes to the age-dependent cartilage loss of functions through the production of hypertrophy-associated catabolic matrix-remodeling enzymes and pro-inflammatory cytokines. Here, we evaluated the effects of the secreted variant of the anti-aging hormone ?-Klotho on cartilage homeostasis during both cartilage formation and OA development. First, we found that ?-Klotho expression was detected during mouse limb development, and transiently expressed during in vitro chondrogenic differentiation of bone marrow-derived mesenchymal stem cells. Genome-wide gene array analysis of chondrocytes from OA patients revealed that incubation with recombinant secreted ?-Klotho repressed expression of the NOS2 and ZIP8/MMP13 catabolic remodeling axis. Accordingly, ?-Klotho expression was reduced in chronically IL1?-treated chondrocytes and in cartilage of an OA mouse model. Finally, in vivo intra-articular secreted ?-Kotho gene transfer delays cartilage degradation in the OA mouse model. Altogether, our results reveal a new tissue homeostatic function for this anti-aging hormone in protecting against OA onset and progression.

SUBMITTER: Chuchana P

PROVIDER: S-EPMC6046234 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Secreted α-Klotho maintains cartilage tissue homeostasis by repressing <i>NOS2</i> and <i>ZIP8-MMP13</i> catabolic axis.

Chuchana Paul P Mausset-Bonnefont Anne-Laure AL Mathieu Marc M Espinoza Francisco F Teigell Marisa M Toupet Karine K Ripoll Chantal C Djouad Farida F Noel Danièle D Jorgensen Christian C Brondello Jean-Marc JM

Aging 20180601 6

Progressive loss of tissue homeostasis is a hallmark of numerous age-related pathologies, including osteoarthritis (OA). Accumulation of senescent chondrocytes in joints contributes to the age-dependent cartilage loss of functions through the production of hypertrophy-associated catabolic matrix-remodeling enzymes and pro-inflammatory cytokines. Here, we evaluated the effects of the secreted variant of the anti-aging hormone α-Klotho on cartilage homeostasis during both cartilage formation and O ...[more]

PMID: 29920476

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Project description:INTRODUCTION: Adiponectin has been implicated in the pathogenesis of osteoarthritis (OA). We studied the effects of adiponectin on the OA cartilage homeostasis. METHODS: Immunohistochemical 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 ?g/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. RESULTS: The 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. CONCLUSIONS: Adiponectin 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.

Dataset Information

Secreted ?-Klotho maintains cartilage tissue homeostasis by repressing NOS2 and ZIP8-MMP13 catabolic axis.

Publications

Secreted α-Klotho maintains cartilage tissue homeostasis by repressing <i>NOS2</i> and <i>ZIP8-MMP13</i> catabolic axis.

Similar Datasets

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