CAAT/enhancer-binding protein-beta (C/EBP¥â) is a transcription factor that regulates interleukin-1¥â (IL-1¥â)-induced catabolic pathways, including the expression of matrix metalloproteinases (MMPs), in chondrocytes. We previously reported that suppressor of cytokine signaling 1 (SOCS1) inhibits IL-1¥â signaling in chondrocytes. However, the effect of SOCS1 on C/EBP¥â has not been explored. To investigate the interaction between SOCS1 and C/EBP¥â, we established human SW1353 cells with overexpression or knockdown of SOCS1 or C/EBP¥â. Both SOCS1 and C/EBP¥â were involved in transcription of MMP-3 and MMP-13. When stimulated with IL-1¥â, C/EBP¥â levels were significantly increased by SOCS1 knockdown and decreased by SOCS1 overexpression. A similar change in IL-1¥â-induced C/EBP¥â expression was observed in SOCS1-transfected human articular chondrocytes. However, C/EBP¥â overexpression or knockdown did not change the levels of IL-1¥â-induced SOCS1. SOCS1 regulated the levels of C/EBP¥â mRNA by ubiquitination of C/EBP¥â as well as transcriptional regulation. Furthermore, it suppressed the phosphorylation of cAMP response element-binding protein (CREB), an active transcription factor of C/EBP¥â. In addition, p38 mitogen-activated protein kinases, a target of SOCS1, was involved in CREB phosphorylation. The chromatin immunoprecipitation assay confirmed that SOCS1 overexpression led to reduced binding of C/EBP¥â to the MMP-13 promoter. Taken together, our results demonstrate that SOCS1 downregulates the p38-CREB-C/EBP¥â pathway resulting in increased expression of MMPs in chondrocytes.
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