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

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.

p-Smad3 differentially regulates the cytological behavior of osteoclasts before and after osteoblasts maturation

“…Similar findings were observed in relevant studies [13,25] . However, TGF-β1 has also inhibited RANKL and promoted OPG expression in the case of 1α,25(OH)2-vitamin D3 stimulation, which reduced osteoclast production in a co-culture environment [15,[26][27] . TGF-β1 was introduced in these studies to activate p-Smad3, the final results may have been interfered with owing to the presence of other TGF-β1-related signaling pathways in addition to the pathway that activates p-Smad3 [28] .…”

“…However, different findings have been reported that TGF-β1 downregulated the RANKL stimulated by 1α,25(OH)2-vitamin D3 and Dex in ST2 cells and inhibited osteoclast differentiation. The inhibition of the RANKL was reversed by blocking Smad2/3 using A83-01 or siRNA [15] . Smad3 has differential regulatory effects on the osteogenic lineage from different origins and osteoblasts at different stages of differentiation.…”

The Relationship between Renin–Angiotensin–Aldosterone System (RAAS) Activity, Osteoporosis and Estrogen Deficiency in Type 2 Diabetes

“…Additionally, in the first phases of osteoblast development, TGF-1β increases the synthesis of extracellular bone matrix protein by osteoblasts, thus maintaining bone health [134]. Estrogen increases osteoblast proliferation and differentiation by increasing the synthesis of TGF-β1 in osteoblasts [135]. In addition, estrogen inhibits bone loss by encouraging osteoclast apoptosis through a TGF-dependent process [136].…”

Mechanism of TGFβ in Bone Metastases and its Potential Therapeutic Uses

“…TGFβ1 inhibited RANKL expression and osteoclast-supporting activity of osteoblasts/stromal cells induced by D3 and Dex through RXRprotein degradation mediated by the ubiquitin-proteasome system. TGFβ1 exerts complex and biphasic effects on osteoclastogenesis [91]. TGFβ also increases osteoblast lineage RANKL expression, thereby fostering the recruitment of osteoclast precursors [92].…”