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Arthritis Rheum ; 60(1): 143-54, 2009 Jan.
Article in English | MEDLINE | ID: mdl-19116903

ABSTRACT

OBJECTIVE: Two major receptor-activated Smad (R-Smad) signaling pathways, bone morphogenetic protein (BMP) and MAPK, were examined in a model of interleukin-1beta (IL-1beta)-induced cartilage degeneration to investigate the effect of IL-1beta on osteogenic protein 1 (OP-1) signaling in adult human articular chondrocytes. METHODS: Chondrocytes from the ankles of 26 normal human donors were cultured in high-density monolayers in serum-free medium. The effect of IL-1beta on BMP receptors was studied by reverse transcription-polymerase chain reaction and flow cytometry. Phosphorylation of R-Smads was tested in cells treated with IL-1beta (10 ng/ml), OP-1 (100 ng/ml), or the combination of IL-1beta and OP-1. Cell lysates were analyzed by Western blotting with polyclonal antibodies against 2 R-Smad phosphorylation sites (BMP- and MAPK-mediated) or with total, nonphosphorylated R-Smad as a control. To identify which MAPKs play a role in IL-1beta activation of the linker region, chondrocytes were preincubated with specific MAPK inhibitors (PD98059 for MAP/ERK, SP600125 for JNK, and SB203580 for p38). RESULTS: IL-1beta reduced the number of activin receptor-like kinase 2 (ALK-2) and ALK-3 receptors, inhibited expression of Smad1 and Smad6, delayed and prematurely terminated the onset of OP-1-mediated R-Smad phosphorylation, and affected nuclear translocation of R-Smad/Smad4 complexes. The alternative phosphorylation of R-Smad in the linker region via the MAPK pathway (primarily p38 and JNK) was observed to be a possible mechanism through which IL-1beta offsets OP-1 signaling and the response to OP-1. Conversely, OP-1 was found to directly inhibit phosphorylation of p38. CONCLUSION: These findings describe new mechanisms of the crosstalk between OP-1 and IL-1beta in chondrocytes. The study also identifies potential targets for therapeutic interventions in the treatment of cartilage-degenerative processes.


Subject(s)
Bone Morphogenetic Protein 7/metabolism , Chondrocytes/metabolism , Interleukin-1beta/metabolism , MAP Kinase Signaling System/physiology , Adult , Bone Morphogenetic Protein 7/pharmacology , Bone Morphogenetic Protein Receptors/genetics , Bone Morphogenetic Protein Receptors/metabolism , Cartilage, Articular/cytology , Cells, Cultured , Chondrocytes/cytology , Flow Cytometry , Gene Expression/drug effects , Gene Expression/physiology , Humans , Interleukin-1beta/pharmacology , MAP Kinase Signaling System/drug effects , Phosphorylation/drug effects , Phosphorylation/physiology , Smad1 Protein/metabolism , Smad4 Protein/metabolism , Smad6 Protein/metabolism
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