Mechanisms involved in suppression of osteoclast supportive activity by transforming growth factor-β1 via the ubiquitin-proteasome system

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 o...

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Veröffentlicht in:PloS one 2022-02, Vol.17 (2), p.e0262612-e0262612
Hauptverfasser: Inoue, Momoko, Nagai-Yoshioka, Yoshie, Yamasaki, Ryota, Kawamoto, Tatsuo, Nishihara, Tatsuji, Ariyoshi, Wataru
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Sprache:eng
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Zusammenfassung: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0262612