Dlx5 Represses the Transcriptional Activity of PPARγ

Kim, Chae Yul; Cho, Dong Hyeok; Chung, Dong Jin; Lee, Sung Ho; Han, Younho; Lee, Kwang Youl

doi:10.1248/bpb.b21-00245

Cited by 4 publications

(2 citation statements)

References 34 publications

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“…BMP-2, a member of the BMP family of growth factors, is primarily distributed in bone tissue and activates the production of bone formation-specific transcription factors by receiving extracellular stimulatory signals from osteoblasts, thus promoting bone formation [ 23 ], whereas Runx2 is a specific transcription factor for bone formation. BMP-2 can promote osteogenesis by activating ERK1/2 and increasing the expression of Runx2 by elevating its phosphorylation level [ 24 ]. RT-PCR and western blotting revealed that BMP-2 and Runx2 proteins and mRNA expression were significantly decreased in the OVX group, indicating the reduced osteogenic potential of rats following OVX treatment.…”

Section: Discussionmentioning

confidence: 99%

Network Pharmacological Analysis and Animal Experimental Study on Osteoporosis Treatment with GuBen‐ZengGu Granules

Wang

Fan²,

Wen

et al. 2023

Evidence-Based Complementary and Alternative Medicine

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Aim. We explored the molecular pathway and material basis of GuBen-ZengGu granules (GBZGG) in treating osteoporosis using network pharmacology and animal experiments. Methods. The effective active components and potential targets of GBZGG were obtained from the TCMSP database and BATMAN-TCM database. Disease-related genes were obtained from GeneCard, NCBI, and DisGeNET. Next, a protein interaction network was established using the STRING database, and core genes were screened using the MCODE module. Cytoscape 3.8.0 was used to construct the network of component-disease-pathway-target, and KEGG pathway enrichment analyses were performed using the clusterProfiler R package to predict the mechanism of GBZGG in treating osteoporosis. An osteoporosis rat model was established by ovarian excision (OVX), and the partial results of network pharmacology were experimentally verified. Results. Pharmacodynamic results showed that GBZGG increased bone mineral density (BMD) and significantly improved the indexes of femur microstructure in model rats. The network pharmacology results showed that quercetin, luteolin, stigmasterol, angelicin, kaempferol, bakuchiol, bakuchiol, 7-O-methylisomucronulatum, isorhamnetin, formononetin, and beta-sitosterol are the major components of GBZGG, with MAPK1, AKT1, JUN, HSP90AA1, RELA, MAPK14, ESR1, RXRA, FOS, MAPK8, NCOA1, MYC, and IL-6 as its core targets for treating osteoporosis. Biological effects could be exerted by regulating the signaling pathways of fluid shear stress and the signaling pathways of atherosclerosis, advanced glycation end products (AGE-RAGE) of diabetic complications, prostate cancer, interleukin (IL-17), tumor necrosis factor (TNF), hepatitis B, mitogen-activated protein kinase (MAPK), etc. The results of animal experiments showed that GBZGG could reduce the serum levels of IL-6 and TNF-α, increase the expression of bone morphogenetic protein-2 (BMP-2) and runt-related transcription factor 2 (RUNX2) protein, and inhibit the activity of extracellular-regulated protein kinases (ERK1/2) and phosphorylation ERK1/2 (p-ERK1/2) protein. Conclusion. GBZGG reduces the expression of ERK1/2 and p-ERK1/2 proteins and mRNAs through the inhibitory effects on IL-6 and TNF-α and negatively regulates the MAPK/ERK signaling pathway. The osteoporosis model showed that it effectively improved the loss of bone mass and destruction of bone microstructure in rats and maintained a positive balance for bone metabolism.

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Section: Discussionmentioning

confidence: 99%

Network Pharmacological Analysis and Animal Experimental Study on Osteoporosis Treatment with GuBen‐ZengGu Granules

Wang

Fan²,

Wen

et al. 2023

Evidence-Based Complementary and Alternative Medicine

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“…In particular, the undesirable determination of MSC cell fate to the adipogenic lineage is regulated by lineage-specific transcription factors such as runt-related transcription factor 2 (RUNX2) and peroxisome proliferator-activated receptor gamma (PPARγ), which causes an imbalance between osteoblast and adipocytes [ 8 , 9 ]. It has been shown that these two key transcription factors that play important roles in MSC differentiation can be regulated by Distal-Less Homeobox 5 (DLX5), which is known as an enhancer of RUNX2 expression and an inhibitor of PPARγ expression [ 10 – 12 ]. However, few studies have been conducted on how DLX5 expression is regulated during osteoblast differentiation of MSCs.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of the RNA-binding protein PUM2 facilitates MSC-driven bone regeneration and prevents OVX-induced bone loss

Yoon¹,

Choi

Lee

et al. 2023

J Biomed Sci

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Background Although mRNA dysregulation can induce changes in mesenchymal stem cell (MSC) homeostasis, the mechanisms by which post-transcriptional regulation influences MSC differentiation potential remain understudied. PUMILIO2 (PUM2) represses translation by binding target mRNAs in a sequence-specific manner. Methods In vitro osteogenic differentiation assays were conducted using human bone marrow-derived MSCs. Alkaline phosphatase and alizarin red S staining were used to evaluate the osteogenic potential of MSCs. A rat xenograft model featuring a calvarial defect to examine effects of MSC-driven bone regeneration. RNA-immunoprecipitation (RNA-IP) assay was used to determine the interaction between PUM2 protein and Distal-Less Homeobox 5 (DLX5) mRNA. Ovariectomized (OVX) mice were employed to evaluate the effect of gene therapy for postmenopausal osteoporosis. Results Here, we elucidated the molecular mechanism of PUM2 in MSC osteogenesis and evaluated the applicability of PUM2 knockdown (KD) as a potential cell-based or gene therapy. PUM2 level was downregulated during MSC osteogenic differentiation, and PUM2 KD enhanced MSC osteogenic potential. Following PUM2 KD, MSCs were transplanted onto calvarial defects in 12-week-old rats; after 8 weeks, transplanted MSCs promoted bone regeneration. PUM2 KD upregulated the expression of DLX5 mRNA and protein and the reporter activity of its 3'-untranslated region. RNA-IP revealed direct binding of PUM2 to DLX5 mRNA. We then evaluated the potential of adeno-associated virus serotype 9 (AAV9)-siPum2 as a gene therapy for osteoporosis in OVX mice. Conclusion Our findings suggest a novel role for PUM2 in MSC osteogenesis and highlight the potential of PUM2 KD-MSCs in bone regeneration. Additionally, we showed that AAV9-siPum2 is a potential gene therapy for osteoporosis.

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Cell signaling and transcriptional regulation of osteoblast lineage commitment, differentiation, bone formation, and homeostasis

Zhu,

Chen,

Masson

et al. 2024

Cell Discov

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The initiation of osteogenesis primarily occurs as mesenchymal stem cells undergo differentiation into osteoblasts. This differentiation process plays a crucial role in bone formation and homeostasis and is regulated by two intricate processes: cell signal transduction and transcriptional gene expression. Various essential cell signaling pathways, including Wnt, BMP, TGF-β, Hedgehog, PTH, FGF, Ephrin, Notch, Hippo, and Piezo1/2, play a critical role in facilitating osteoblast differentiation, bone formation, and bone homeostasis. Key transcriptional factors in this differentiation process include Runx2, Cbfβ, Runx1, Osterix, ATF4, SATB2, and TAZ/YAP. Furthermore, a diverse array of epigenetic factors also plays critical roles in osteoblast differentiation, bone formation, and homeostasis at the transcriptional level. This review provides an overview of the latest developments and current comprehension concerning the pathways of cell signaling, regulation of hormones, and transcriptional regulation of genes involved in the commitment and differentiation of osteoblast lineage, as well as in bone formation and maintenance of homeostasis. The paper also reviews epigenetic regulation of osteoblast differentiation via mechanisms, such as histone and DNA modifications. Additionally, we summarize the latest developments in osteoblast biology spurred by recent advancements in various modern technologies and bioinformatics. By synthesizing these insights into a comprehensive understanding of osteoblast differentiation, this review provides further clarification of the mechanisms underlying osteoblast lineage commitment, differentiation, and bone formation, and highlights potential new therapeutic applications for the treatment of bone diseases.

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Dlx5 Represses the Transcriptional Activity of PPARγ

Cited by 4 publications

References 34 publications

Network Pharmacological Analysis and Animal Experimental Study on Osteoporosis Treatment with GuBen‐ZengGu Granules

Network Pharmacological Analysis and Animal Experimental Study on Osteoporosis Treatment with GuBen‐ZengGu Granules

Downregulation of the RNA-binding protein PUM2 facilitates MSC-driven bone regeneration and prevents OVX-induced bone loss

Cell signaling and transcriptional regulation of osteoblast lineage commitment, differentiation, bone formation, and homeostasis

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