Abstract:Osteoporosis (OP) is a serious metabolic disease that, due to the increased number or function of osteoclasts, results in increased bone brittleness and, therefore, fragile fracture. Some recent studies report the importance of the transforming growth factor β (TGFβ) pathway in bone homeostasis. RepSox is a small molecule inhibitor of TGFβRI that has a wide range of potential application in clinical medicine, except OP. The aim of our study is to evaluate the effects of RepSox on the differentiation and bone r… Show more
“…As a result, THF did not significantly differ in ALP activity and bone mineral nodules of osteoblastic changes in LPS-stimulated MC3T3-E1 osteoblast-like cells. These results suggest that THF does not affect osteoblast differentiation and osteoclast specific gene expression and suggests the possibility of osteolytic diseases associated with osteoclasts, such as RepSox previously studied (Mei et al, 2018).…”
Section: Effect Of Thf On Bone Formation Of Osteoblasts Stimulated mentioning
The balance between the osteoblasts and the osteoclasts is important for the maintenance of the skeleton of the human body. The osteoclasts absorb bone after differentiated into polymorphonuclear cells by the fusion of monocytes/macrophages. We have found that 6,7,4′‐Trihydroxyflavone (THF), a compound from the heartwood of Dalbergia Odorifera inhibits receptor activator of NF‐κB ligand (RANKL)‐induced osteoclast differentiation, actin ring formation, and bone resorption in RAW 264.7 cells and bone marrow macrophage. THF significantly inhibited the c‐Jun‐N‐terminal kinase signaling pathway without affecting extracellular signal‐regulated kinase, p38, and AKT signaling. Moreover, THF inhibited the expression of c‐Fos, nuclear factor‐activated T cells cytoplasm 1, cathepsin K, and c‐src by RANKL. We used a lipopolysaccharide (LPS)‐induced bone loss model in mice. Consequently, bone volume per tissue volume, trabecular number's reduction was recovered in THF‐treated mice, and trabecular separation's augmentation was also attenuated by THF administration. In summary, THF inhibits RANKL‐induced osteoclast differentiation by MAPK signaling pathway and inhibits bone resorption by destroying the actin ring in mature osteoclasts. THF also prevented LPS‐induced bone loss in a mice model. Thus, THF may be useful in the treatment of bone diseases associated with excessive osteoclast differentiation and bone resorption.
“…As a result, THF did not significantly differ in ALP activity and bone mineral nodules of osteoblastic changes in LPS-stimulated MC3T3-E1 osteoblast-like cells. These results suggest that THF does not affect osteoblast differentiation and osteoclast specific gene expression and suggests the possibility of osteolytic diseases associated with osteoclasts, such as RepSox previously studied (Mei et al, 2018).…”
Section: Effect Of Thf On Bone Formation Of Osteoblasts Stimulated mentioning
The balance between the osteoblasts and the osteoclasts is important for the maintenance of the skeleton of the human body. The osteoclasts absorb bone after differentiated into polymorphonuclear cells by the fusion of monocytes/macrophages. We have found that 6,7,4′‐Trihydroxyflavone (THF), a compound from the heartwood of Dalbergia Odorifera inhibits receptor activator of NF‐κB ligand (RANKL)‐induced osteoclast differentiation, actin ring formation, and bone resorption in RAW 264.7 cells and bone marrow macrophage. THF significantly inhibited the c‐Jun‐N‐terminal kinase signaling pathway without affecting extracellular signal‐regulated kinase, p38, and AKT signaling. Moreover, THF inhibited the expression of c‐Fos, nuclear factor‐activated T cells cytoplasm 1, cathepsin K, and c‐src by RANKL. We used a lipopolysaccharide (LPS)‐induced bone loss model in mice. Consequently, bone volume per tissue volume, trabecular number's reduction was recovered in THF‐treated mice, and trabecular separation's augmentation was also attenuated by THF administration. In summary, THF inhibits RANKL‐induced osteoclast differentiation by MAPK signaling pathway and inhibits bone resorption by destroying the actin ring in mature osteoclasts. THF also prevented LPS‐induced bone loss in a mice model. Thus, THF may be useful in the treatment of bone diseases associated with excessive osteoclast differentiation and bone resorption.
“…As shown in figure 1G, the expression levels of PTPN14 positively correlated with TGFBR1 in RA (Spearman γ=0.8455, p<0.01) and OA FLS (Spearman γ=0.8364, p<0.01) and THBS1 in RA FLS (Spearman γ=0.6545, p<0.05) and OA FLS (Spearman γ=0.6727, p<0.05), while there was no correlation between the expression levels of PTPN14 and TGFB1 (data not shown). Inhibition of TGFβ signalling using two selective TGFβRI antagonists SB50512428 and RepSox,29 reduced PTPN14 expression in unstimulated RA FLS (p<0.05, p<0.01, respectively) (figure 1H,I) suggesting that enhanced autocrine stimulation with TGFβ plays a role in the upregulation of PTPN14 in RA FLS. However, additional unknown pathways likely contribute to enhance PTPN14 mRNA and protein levels in RA FLS in vitro and in the rheumatoid joint.…”
ObjectiveWe aimed to understand the role of the tyrosine phosphatase PTPN14—which in cancer cells modulates the Hippo pathway by retaining YAP in the cytosol—in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA).MethodsGene/protein expression levels were measured by quantitative PCR and/or Western blotting. Gene knockdown in RA FLS was achieved using antisense oligonucleotides. The interaction between PTPN14 and YAP was assessed by immunoprecipitation. The cellular localisation of YAP and SMAD3 was examined via immunofluorescence. SMAD reporter studies were carried out in HEK293T cells. The RA FLS/cartilage coimplantation and passive K/BxN models were used to examine the role of YAP in arthritis.ResultsRA FLS displayed overexpression of PTPN14 when compared with FLS from patients with osteoarthritis (OA). PTPN14 knockdown in RA FLS impaired TGFβ-dependent expression of MMP13 and potentiation of TNF signalling. In RA FLS, PTPN14 formed a complex with YAP. Expression of PTPN14 or nuclear YAP—but not of a non-YAP-interacting PTPN14 mutant—enhanced SMAD reporter activity. YAP promoted TGFβ-dependent SMAD3 nuclear localisation in RA FLS. Differences in epigenetic marks within Hippo pathway genes, including YAP, were found between RA FLS and OA FLS. Inhibition of YAP reduced RA FLS pathogenic behaviour and ameliorated arthritis severity.ConclusionIn RA FLS, PTPN14 and YAP promote nuclear localisation of SMAD3. YAP enhances a range of RA FLS pathogenic behaviours which, together with epigenetic evidence, points to the Hippo pathway as an important regulator of RA FLS behaviour.
“…MAPK signaling pathways, including the ERK, JNK and p38 sub-pathways, are some of the key pathways involved in adipogenesis ( 30 ). In the present study, RepSox reduced the phosphorylation of Smad3 ( Fig.…”
Previous reports have demonstrated that RepSox can function as a replacement for cMyc and Sox2 in the reprogramming of cells into induced pluripotent stem cells (iPSCs), as well as increasing the levels of bone morphogenetic protein (BMP)-3 and inducing the phosphorylation of Smad1 in mouse embryonic stem cells. In the present study, it was demonstrated that RepSox caused the visible morphological transformation of sheep fibroblasts; however, no significant alterations in cell proliferation, apoptosis or chromosome aberrations were observed. Moreover, RepSox increased the plasticity of long-term cryopreserved sheep fibroblasts, and further promoted differentiation into adipocytes. RepSox treatment led to a notable decrease in the expression of components of the transforming growth factor (TGF)-β signaling pathway, particularly Smad2/3 phosphorylation. RepSox also activated the BMP pathway, promoted the reprogramming of cells from fibroblasts into adipocytes and induced mesenchymal-epithelial transition. It is worth noting that RepSox notably increased the expression of octamer-binding transcription factor 4 and L-Myc, whereas Sox2 and Nanog expression were not detected. The results of high-throughput RNA sequencing revealed that the levels of differentially expressed genes (DEGs) involved in various metabolic processes were markedly upregulated in the RepSox-treated fibroblasts, while the DEGs in the majority of signaling pathways were markedly downregulated. On the whole, the present study demonstrates that RepSox can promote the plasticity of sheep fibroblasts and facilitates the differentiation of adipocytes via increasing BMP expression and inhibiting the activation of the TGF-β signaling pathway.
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