RRC ID 69854
Author Inoue M, Nagai-Yoshioka Y, Yamasaki R, Kawamoto T, Nishihara T, Ariyoshi W.
Title Mechanisms involved in suppression of osteoclast supportive activity by transforming growth factor-β1 via the ubiquitin-proteasome system.
Journal PLoS One
Abstract Orthodontic treatment requires the regulation of bone remodeling in both compression and tension sides. Transforming growth factor-β1 (TGF-β1) is an important coupling factor for bone remodeling. However, the mechanism underlying the TGF-β1-mediated regulation of the osteoclast-supporting activity of osteoblasts and stromal cells remain unclear. The current study investigated the effect of TGF-β1 on receptor activator of nuclear factor kappa-B ligand (RANKL) expression in stromal cells induced by 1α,25(OH)2D3 (D3) and dexamethasone (Dex). TGF-β1 downregulated the expression of RANKL induced by D3 and Dex in mouse bone marrow stromal lineage, ST2 cells. Co-culture system revealed that TGF-β1 suppressed osteoclast differentiation from bone marrow cell induced by D3 and Dex-activated ST2 cells. The inhibitory effect of TGF-β1 on RANKL expression was recovered by inhibiting the interaction between TGF-β1 and the TGF-β type I/activin receptor or by downregulating of smad2/3 expression. Interestingly, TGF-β1 degraded the retinoid X receptor (RXR)-α protein which forms a complex with vitamin D receptor (VDR) and regulates transcriptional activity of RANKL without affecting nuclear translocation of VDR and phosphorylation of signal transducer and activator of transcription3 (STAT3). The degradation of RXR-α protein by TGF-β1 was recovered by a ubiquitin-proteasome inhibitor. We also observed that poly-ubiquitination of RXR-α protein was induced by TGF-β1 treatment. These results indicated that TGF-β1 downregulates RANKL expression and the osteoclast-supporting activity of osteoblasts/stromal cells induced by D3 and Dex through the degradation of the RXR-α protein mediated by ubiquitin-proteasome system.
Volume 17(2)
Pages e0262612
Published 2022-1-1
DOI 10.1371/journal.pone.0262612
PII PONE-D-21-26829
PMID 35196318
PMC PMC8865688
MeSH Animals Bone Marrow Cells / drug effects Bone Marrow Cells / metabolism Cell Differentiation / drug effects Cell Differentiation / genetics Cell Line Coculture Techniques Leupeptins / pharmacology Macrophages / drug effects Macrophages / metabolism Male Mice Osteoclasts / cytology Osteoclasts / drug effects* Osteoclasts / metabolism* Proteasome Endopeptidase Complex / metabolism* Proteasome Inhibitors / pharmacology Recombinant Proteins / pharmacology Signal Transduction / drug effects* Signal Transduction / genetics Smad2 Protein / genetics Smad2 Protein / metabolism Smad3 Protein / genetics Smad3 Protein / metabolism Stromal Cells / drug effects Stromal Cells / metabolism Transfection Transforming Growth Factor beta1 / pharmacology* Ubiquitin / metabolism* Ubiquitination / drug effects* Ubiquitination / genetics
IF 2.74
Human and Animal Cells ST2(RCB0224)