Abstract
BackgroundThe purpose of the current study was to explore the role and underlying mechanism of cellular retinoic acid binding protein 2 (CRABP2) in dexamethasone (DEX)-induced apoptosis in human osteoblast cells.MethodsGSE10311 was downloaded from the Gene Expression Omnibus (GEO) database to identify the differentially expressed genes (DEGs) by the limma/R package. Primary human osteoblast was isolated and treated with different concentration of DEX (0, 10-8, 10-7, 10-6, 10-5, and 10-4 mol/L), and cell viability and flow cytometry were used to detect cell proliferation and apoptosis. A CRABP2 overexpression plasmid (oe-CRABP2) was used to overexpress CRABP2, and western blotting was conducted to detect protein expression.ResultsWe found that CRABP2 was downregulated in the DEX-treated group. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that DEGs were associated with PI3K/Akt signaling pathway. DEX downregulated CRABP2 gene and protein expression, inhibited viability, and induced human osteoblast apoptosis. Overexpression of CRABP2 reversed DEX-induced apoptosis in human osteoblast. Moreover, overexpression of CRABP2 delayed the progression of DEX-induced osteonecrosis of the femoral head (ONFH) animal model.ConclusionIn conclusion, CRABP2 is effective at inhibiting DEX-induced human osteoblast apoptosis and delayed ONFH progression.
Highlights
Glucocorticoids are important drugs in the treatment of many inflammatory, autoimmune, allergic diseases, cancer, and organ transplantations in humans and animals [1,2,3,4]
All differentially expressed genes (DEGs) were imported to DAVID software, and Gene Ontology (GO) analysis results demonstrated that upregulated and downregulated DEGs were enriched in the following biological processes (BP): Inflammatory response, cellular response to cadmium ion, negative regulation of growth, oxidation-reduction process, cellular response to zinc ion, cellular component (CC): extracellular space, integral component of plasma membrane, extracellular region, extracellular exosome, proteinaceous extracellular matrix, and molecular function (MF): receptor binding, indanol dehydrogenase activity, aldo-keto reductase (NADP) activity, oxidoreductase activity, alditol:NADP+ 1-oxidoreductase activity, cytokine receptor activity, and growth factor activity (Fig. 1d)
The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the DEGs were significantly enriched in mineral absorption, complement coagulation cascades, rheumatoid arthritis, drug metabolism-cytochrome P450, TNF signaling pathway, inflammatory mediator regulation of TRP channels, FoxO signaling pathway, Chagas disease, cytokine-cytokine receptor interaction, and pathway in cancer (Fig. 1e)
Summary
Glucocorticoids are important drugs in the treatment of many inflammatory, autoimmune, allergic diseases, cancer, and organ transplantations in humans and animals [1,2,3,4]. Cellular retinoic acid-binding proteins, CRABP1 and CRABP2, are small cytosolic proteins that belong to a family of two isotypes. Wu et al [15] found that CRABP2 promotes metastasis of lung cancer cells via HuR and Integrin β1/FAK/ERK signaling pathway. The role of CRABP2 in regulating dexamethasone induced osteoblast apoptosis and ONFH was unknown. The purpose of the current study was to explore the role and underlying mechanism of cellular retinoic acid binding protein 2 (CRABP2) in dexamethasone (DEX)-induced apoptosis in human osteoblast cells
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