ABSTRACT
CIZ/NMP4 (Cas interacting zinc finger protein, Nmp4, Zfp384) is a transcription factor that is known to regulate matrix related-proteins. To explore the possible pathophysiological role of CIZ/NMP4 in arthritis, we examined CIZ/NMP4 expression in articular cartilage in arthritis model. CIZ/NMP4 was expressed in the articular chondrocytes of mice at low levels while its expression was enhanced when arthritis was induced. Arthritis induction increased clinical score in wild type mice. In contrast, CIZ/NMP4 deficiency suppressed such rise in the levels of arthritis score and swelling of soft tissue. CIZ/NMP4 deficiency also reduced invasion of inflammatory cells in joint tissue. Quantitative PCR analyses of mRNA from joints revealed that arthritis-induced increase in expressions of IL-1ß was suppressed by CIZ/NMP4 deficiency. CIZ/NMP4 bound to IL-1ß promoter and activated its transcription. The increase in CIZ/NMP4 in arthritis was also associated with enhancement in bone resorption and cartilage matrix degradation. In fact, RANKL, a signaling molecule prerequisite for osteoclastogenesis and, MMP-3, a clinical marker for arthritis were increased in joints upon arthritis induction. In contrast, CIZ/NMP4 deficiency suppressed the arthritis-induced increase in bone resorption, expression of RANKL and MMP-3 mRNA. Thus, CIZ/NMP4 plays a role in the development of arthritis at least in part through regulation of key molecules related to the arthritis.
Subject(s)
Arthritis, Experimental/genetics , Cartilage, Articular/immunology , Matrix Metalloproteinase 3/immunology , Nuclear Matrix-Associated Proteins/immunology , RANK Ligand/immunology , Transcription Factors/immunology , Animals , Arthritis, Experimental/chemically induced , Arthritis, Experimental/immunology , Arthritis, Experimental/pathology , Autoantibodies/biosynthesis , Bone Resorption , Cartilage, Articular/pathology , Chondrocytes/immunology , Chondrocytes/pathology , Female , Gene Expression Regulation , Glucose-6-Phosphate Isomerase/antagonists & inhibitors , Glucose-6-Phosphate Isomerase/genetics , Glucose-6-Phosphate Isomerase/immunology , Immune Sera/administration & dosage , Interleukin-1beta/genetics , Interleukin-1beta/immunology , Joints/immunology , Joints/pathology , Male , Matrix Metalloproteinase 3/genetics , Mice , Mice, Knockout , Nuclear Matrix-Associated Proteins/deficiency , Nuclear Matrix-Associated Proteins/genetics , Promoter Regions, Genetic , RANK Ligand/genetics , Severity of Illness Index , Signal Transduction , Transcription Factors/deficiency , Transcription Factors/genetics , Transcription, GeneticABSTRACT
Over the past two decades, fluoride effects on osteoclasts have been evaluated; however, its molecular mechanisms remain unclear. In this study, we investigated the effect of fluoride on osteoclast formation, function, and regulation using osteoclasts formed from mice bone marrow macrophages treated with the receptor activator of NF-κB ligand and macrophage colony-stimulating factor. Our data showed that fluoride levels ≤ 8 mg/L had no effect on osteoclast formation; however, it significantly reduced osteoclast resorption at 0.5 mg/L. Fluoride activity on bone resorption occurred through the inhibition of nuclear factor of active T cells (NFAT) c1 expression. Furthermore, the expression of its downstream genes, including the dendritic cell-specific transmembrane protein, c-Src, the d2 isoform of vacuolar (H+) ATPase v0 domain, matrix metalloproteinase 9, and cathepsin K were decreased, leading to impaired osteoclast acidification, reduced secretion of proteolytic enzymes, and decreased bone resorption. In summary, our results suggested that fluoride has different roles in osteoclast formation and function. Fluoride ≤ 8 mg/L did not impact osteoclast formation; however, it significantly decreased the resorption activity of newly formed osteoclasts. The molecular mechanism of fluoride action may involve inhibition of NFATc1 and its downstream genes.