OBJECTIVE: S100A4 has been shown to be increased in osteoarthritic (OA) cartilage and to stimulate chondrocytes to produce matrix metalloproteinase 13 (MMP-13) through activation of the receptor for advanced glycation end products (RAGE). The aim of this study was to examine the mechanism of S100A4 secretion by chondrocytes. METHODS: Human articular chondrocytes isolated from ankle cartilage were stimulated with 10 ng/ml of interleukin-1beta (IL-1beta), IL-6, IL-7, or IL-8. Cells were pretreated with either a JAK-3 inhibitor, brefeldin A, or cycloheximide. Immunoblotting with phospho-specific antibodies was used to determine the activation of signaling proteins. Secretion of S100A4 was measured in conditioned media by immunoblotting, and MMP-13 was measured by enzyme-linked immunosorbent assay. RESULTS: Chondrocyte secretion of S100A4 was observed after treatment with IL-6 or IL-8 but was much greater in cultures treated with equal amounts of IL-7 and was not observed after treatment with IL-1beta. IL-7 activated the JAK/STAT pathway, with increased phosphorylation of JAK-3 and STAT-3, leading to increased production of S100A4 and MMP-13. Overexpression of a dominant-negative RAGE construct inhibited the IL-7-mediated production of MMP-13. Pretreatment of chondrocytes with a JAK-3 inhibitor or with cycloheximide blocked the IL-7-mediated secretion of S100A4, but pretreatment with brefeldin A did not. CONCLUSION: IL-7 stimulates chondrocyte secretion of S100A4 via activation of JAK/STAT signaling, and then S100A4 acts in an autocrine manner to stimulate MMP-13 production via RAGE. Since both IL-7 and S100A4 are up-regulated in OA cartilage and can stimulate MMP-13 production by chondrocytes, this signaling pathway could contribute to cartilage destruction during the development of OA.
OBJECTIVE:S100A4 has been shown to be increased in osteoarthritic (OA) cartilage and to stimulate chondrocytes to produce matrix metalloproteinase 13 (MMP-13) through activation of the receptor for advanced glycation end products (RAGE). The aim of this study was to examine the mechanism of S100A4 secretion by chondrocytes. METHODS:Human articular chondrocytes isolated from ankle cartilage were stimulated with 10 ng/ml of interleukin-1beta (IL-1beta), IL-6, IL-7, or IL-8. Cells were pretreated with either a JAK-3 inhibitor, brefeldin A, or cycloheximide. Immunoblotting with phospho-specific antibodies was used to determine the activation of signaling proteins. Secretion of S100A4 was measured in conditioned media by immunoblotting, and MMP-13 was measured by enzyme-linked immunosorbent assay. RESULTS: Chondrocyte secretion of S100A4 was observed after treatment with IL-6 or IL-8 but was much greater in cultures treated with equal amounts of IL-7 and was not observed after treatment with IL-1beta. IL-7 activated the JAK/STAT pathway, with increased phosphorylation of JAK-3 and STAT-3, leading to increased production of S100A4 and MMP-13. Overexpression of a dominant-negative RAGE construct inhibited the IL-7-mediated production of MMP-13. Pretreatment of chondrocytes with a JAK-3 inhibitor or with cycloheximide blocked the IL-7-mediated secretion of S100A4, but pretreatment with brefeldin A did not. CONCLUSION:IL-7 stimulates chondrocyte secretion of S100A4 via activation of JAK/STAT signaling, and then S100A4 acts in an autocrine manner to stimulate MMP-13 production via RAGE. Since both IL-7 and S100A4 are up-regulated in OA cartilage and can stimulate MMP-13 production by chondrocytes, this signaling pathway could contribute to cartilage destruction during the development of OA.
Authors: M Grigorian; S Andresen; E Tulchinsky; M Kriajevska; C Carlberg; C Kruse; M Cohn; N Ambartsumian; A Christensen; G Selivanova; E Lukanidin Journal: J Biol Chem Date: 2001-03-05 Impact factor: 5.157
Authors: N Ambartsumian; J Klingelhöfer; M Grigorian; C Christensen; M Kriajevska; E Tulchinsky; G Georgiev; V Berezin; E Bock; J Rygaard; R Cao; Y Cao; E Lukanidin Journal: Oncogene Date: 2001-08-02 Impact factor: 9.867
Authors: V Novitskaya; M Grigorian; M Kriajevska; S Tarabykina; I Bronstein; V Berezin; E Bock; E Lukanidin Journal: J Biol Chem Date: 2000-12-29 Impact factor: 5.157
Authors: B Moradi; N Rosshirt; E Tripel; J Kirsch; A Barié; F Zeifang; T Gotterbarm; S Hagmann Journal: Clin Exp Immunol Date: 2015-04 Impact factor: 4.330