Fractalkine functions as a chemoattractant for osteoarthritis synovial fibroblasts and stimulates phosphorylation of mitogen-activated protein kinases and Akt

Fractalkine (FKN/CX3CL1) has been detected in synovial fluids from osteoarthritis (OA) patients. Additionally, low-level expression of the FKN receptor, CX3CR1, has been demonstrated in OA synovial lining. This study aimed to determine a biological function for this ligand/receptor pair in OA and to...

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Published in:	Clinical and experimental immunology Vol. 156; no. 2; pp. 312 - 319
Main Authors:	Klosowska, K, Volin, M.V, Huynh, N, Chong, K.K, Halloran, M.M, Woods, J.M
Format:	Journal Article
Language:	English
Published:	Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01-05-2009 Blackwell Publishing Ltd Blackwell Blackwell Science Inc
Subjects:	Actins - analysis Aged Analytical, structural and metabolic biochemistry Biological and medical sciences Blotting, Western - methods Chemokine CX3CL1 - metabolism Chemokine CX3CL1 - pharmacology Chemotaxis CX3C Chemokine Receptor 1 Diseases of the osteoarticular system Extracellular Signal-Regulated MAP Kinases - metabolism Female fibroblast fibroblasts Fibroblasts - metabolism Fibroblasts - pathology Fractalkine/CX3CL1 Fundamental and applied biological sciences. Psychology Humans JNK Mitogen-Activated Protein Kinases - metabolism Male MAP Kinase Signaling System - physiology MAPK Medical sciences Middle Aged migration Miscellaneous. Osteoarticular involvement in other diseases Mitogen-Activated Protein Kinases - metabolism Osteoarthritis Osteoarthritis - metabolism Osteoarthritis - pathology p38 Mitogen-Activated Protein Kinases - metabolism Phosphorylation Proto-Oncogene Proteins c-akt - metabolism Receptors, Cytokine - metabolism Receptors, HIV - metabolism Staining and Labeling Synovial Membrane - chemistry Synovial Membrane - metabolism Synovial Membrane - pathology Translational Studies Phosphorylation CX3C chemokine Enzyme Transferases Diseases of the osteoarticular system Akt protein kinase Mitogen-activated protein kinase Biochemistry MAPK Chemotaxis Fractalkine/CX3CL1 OA Synovial membrane Arthropathy migration Degenerative disease Fractalkine Osteoarthritis Fibroblast Cell migration
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Summary:	Fractalkine (FKN/CX3CL1) has been detected in synovial fluids from osteoarthritis (OA) patients. Additionally, low-level expression of the FKN receptor, CX3CR1, has been demonstrated in OA synovial lining. This study aimed to determine a biological function for this ligand/receptor pair in OA and to assess a potential signalling mechanism for FKN in this predominant synovial lining cell type, using chemotaxis assays, Western blotting and F-actin staining. Chemotaxis assays demonstrate that the chemokine domain of FKN effectively induces migration of OA fibroblasts. Consistent with this finding, visualization of F-actin demonstrates that 1 or 10 nM FKN induces noticeable reorganization of cytoskeletal structure in OA fibroblasts after 30 min stimulation with a maximal enhancement at approximately 2 h. In addition, Western blotting analysis demonstrates that FKN stimulates phosphorylation of the mitogen-activated protein (MAP) kinases p38, c-Jun N-terminal kinase (JNK) and extracellular-regulated kinase (ERK) 1/2 as well as the serine-threonine kinase Akt at Ser 473 and Thr 308. All these phosphorylation events occur in a time-dependent manner, with little or no activation within 1 min, and maximal activation occurring typically between 5 and 30 min. Moreover, inhibition of ERK 1/2 significantly reduces FKN-induced OA fibroblast migration. These results suggest that FKN is a novel chemoattractant for OA fibroblasts, consistent with FKN-induced alterations in cytoskeletal structure. In addition, FKN induces OA fibroblast signalling via the MAP kinases p38, JNK and ERK 1/2, as well as Akt.
Bibliography:	http://dx.doi.org/10.1111/j.1365-2249.2009.03903.x ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0009-9104 1365-2249
DOI:	10.1111/j.1365-2249.2009.03903.x