Icariin promotes osteoblastic differentiation in OVX mice via MAPK signaling pathway revealed by profiling

Objective: Icariin (ICA), an extract from epimedium, has been reported to be effective in promoting bone formation. The objective of the study is to search for the molecular targets of ICA in bone mesenchymal stem cells (bMSCs) from the mice with ovariectomy (OVX)-induced osteoporosis. Methods: Six-month-old Imprinting Control Region (ICR) mice that underwent OVX were treated with ICA. After three months, bone mass was evaluated by microcomputed tomography, morphometry and immunohistological detection. bMSCs were isolated from the femur and tibia to observe the self-renewal and differentiation capacities using colony-forming unit fibroblastic (CFU-F), colony-forming unit adipocyte (CFU-Adipo) and alkaline phosphatase (ALP) staining. In addition, microarray of bMSCs ex vivo was measured two weeks after ICA treatment and analyzed by heatmap and pathway analysis. The signaling pathway was further explored by western blot assay and inhibitors of p38 and ERK: SB203508 and PD98059. Results: [Formula: see text]CT displayed a decrease in bone mass for three months after OVX. ICA treatment increased the trabecular thickness (Tb.Th), osteoblast number while decreased osteoclast number, elevating osteocalcin (OC) protein levels in vivo and facilitating the self-renewal and osteoblastic differentiation of bMSCs ex vivo. Microarray data indicated ICA rescued several gene expressions that were dysregulated by OVX. Pathway analysis revealed that the core genes acted by ICA were highly involved in MAPK signaling pathway. Further study demonstrated ICA suppressed ERK while stimulated p38 phosphorylation to promote osteoblastic differentiation in vitro. Conclusion: ICA promotes osteoblastic differentiation of bMSCs in OVX mice. MAPK signaling pathway might be involved in the process.

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Er-Xian Decoction Stimulates Osteoblastic Differentiation of Bone Mesenchymal Stem Cells in Ovariectomized Mice and Its Gene Profile Analysis

Stem Cells International ◽

10.1155/2016/4079210 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 5

Author(s):

Shufen Liu ◽

Jianhua Huang ◽

Jing Wang ◽

Yongjian Zhao ◽

Sheng Lu ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Bone Mass ◽

Ex Vivo ◽

Osteoblastic Differentiation ◽

The Self ◽

Bone Mesenchymal Stem Cells ◽

Self Renewal ◽

Colony Forming Unit

We studied the bone mesenchymal stem cells (bMSCs) and gene profiles regulated byEr-Xian Decoction(EXD), a traditional Chinese herbal formula widely used for postmenopausal osteoporosis treatment. Six-month-old female Imprinting Control Region mice that underwent ovariectomy were treated with EXD. After 3 months, bone mass was evaluated byμCT and histological and immunohistochemical detection. The self-renewal and differentiation capacities of bMSCs were evaluated by colony-forming unit-fibroblastic, colony-forming unit-adipocyte, and alkaline phosphatase staining. In addition, the expression of 26991 genes of bMSCsex vivoat 2 weeks after EXD-treatment or of bMSCsin vitroafter exposure to conditioned serum from EXD-treated rats was measured and analyzed using NimbleGen Gene Expression Profiling and Cluster and pathway analysis. EXD treatment increased bone mass, elevating osteocalcin protein levelsin vivoand facilitating the self-renewal and osteoblastic differentiation of bMSCsex vivo. EXD rescued several gene expressions that were dysregulated by OVX. These genes overlapped and their functions were involved in ten pathways betweenex vivoandin vitroexperiments. EXD exerts an osteogenic effect on bMSCs in OVX induced osteoporotic mice. Our results contribute to further study of its molecular mechanism and traditional use in the treatment of postmenopausal osteoporosis.

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Chronic mucocutaneous candidiasis and connective tissue disorder in humans with impaired JNK1-dependent responses to IL-17A/F and TGF-β

Science Immunology ◽

10.1126/sciimmunol.aax7965 ◽

2019 ◽

Vol 4 (41) ◽

pp. eaax7965 ◽

Cited By ~ 11

Author(s):

Juan Li ◽

Marco Ritelli ◽

Cindy S. Ma ◽

Geetha Rao ◽

Tanwir Habib ◽

...

Keyword(s):

Connective Tissue ◽

Signaling Pathway ◽

Ex Vivo ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Chronic Mucocutaneous Candidiasis ◽

Connective Tissues ◽

Ehlers Danlos Syndrome ◽

Mucocutaneous Candidiasis ◽

Transcriptional Pattern

Genetic etiologies of chronic mucocutaneous candidiasis (CMC) disrupt human IL-17A/F–dependent immunity at mucosal surfaces, whereas those of connective tissue disorders (CTDs) often impair the TGF-β–dependent homeostasis of connective tissues. The signaling pathways involved are incompletely understood. We report a three-generation family with an autosomal dominant (AD) combination of CMC and a previously undescribed form of CTD that clinically overlaps with Ehlers-Danlos syndrome (EDS). The patients are heterozygous for a private splice-site variant of MAPK8, the gene encoding c-Jun N-terminal kinase 1 (JNK1), a component of the MAPK signaling pathway. This variant is loss-of-expression and loss-of-function in the patients’ fibroblasts, which display AD JNK1 deficiency by haploinsufficiency. These cells have impaired, but not abolished, responses to IL-17A and IL-17F. Moreover, the development of the patients’ TH17 cells was impaired ex vivo and in vitro, probably due to the involvement of JNK1 in the TGF-β–responsive pathway and further accounting for the patients’ CMC. Consistently, the patients’ fibroblasts displayed impaired JNK1- and c-Jun/ATF-2–dependent induction of key extracellular matrix (ECM) components and regulators, but not of EDS-causing gene products, in response to TGF-β. Furthermore, they displayed a transcriptional pattern in response to TGF-β different from that of fibroblasts from patients with Loeys-Dietz syndrome caused by mutations of TGFBR2 or SMAD3, further accounting for the patients’ complex and unusual CTD phenotype. This experiment of nature indicates that the integrity of the human JNK1-dependent MAPK signaling pathway is essential for IL-17A– and IL-17F–dependent mucocutaneous immunity to Candida and for the TGF-β–dependent homeostasis of connective tissues.

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Circular RNA CDR1as regulates osteoblastic differentiation of periodontal ligament stem cells via the miR-7/GDF5/SMAD and p38 MAPK signaling pathway

Stem Cell Research & Therapy ◽

10.1186/s13287-018-0976-0 ◽

2018 ◽

Vol 9 (1) ◽

Cited By ~ 66

Author(s):

Xiaobei Li ◽

Yunfei Zheng ◽

Yan Zheng ◽

Yiping Huang ◽

Yixin Zhang ◽

...

Keyword(s):

Stem Cells ◽

Signaling Pathway ◽

P38 Mapk ◽

Periodontal Ligament ◽

Circular Rna ◽

Osteoblastic Differentiation ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Periodontal Ligament Stem Cells

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MAPK: A Key Player in the Development and Progression of Stroke

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666200613223018 ◽

2020 ◽

Vol 19 (4) ◽

pp. 248-256

Author(s):

Yangmin Zheng ◽

Ziping Han ◽

Haiping Zhao ◽

Yumin Luo

Keyword(s):

Ischemic Stroke ◽

Signaling Pathway ◽

Complex Disease ◽

Therapeutic Targets ◽

Cell Types ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Effective Prevention ◽

Prevention And Treatment ◽

Different Cell Types

Conclusion: Stroke is a complex disease caused by genetic and environmental factors, and its etiological mechanism has not been fully clarified yet, which brings great challenges to its effective prevention and treatment. MAPK signaling pathway regulates gene expression of eukaryotic cells and basic cellular processes such as cell proliferation, differentiation, migration, metabolism and apoptosis, which are considered as therapeutic targets for many diseases. Up to now, mounting evidence has shown that MAPK signaling pathway is involved in the pathogenesis and development of ischemic stroke. However, the upstream kinase and downstream kinase of MAPK signaling pathway are complex and the influencing factors are numerous, the exact role of MAPK signaling pathway in the pathogenesis of ischemic stroke has not been fully elucidated. MAPK signaling molecules in different cell types in the brain respond variously after stroke injury, therefore, the present review article is committed to summarizing the pathological process of different cell types participating in stroke, discussed the mechanism of MAPK participating in stroke. We further elucidated that MAPK signaling pathway molecules can be used as therapeutic targets for stroke, thus promoting the prevention and treatment of stroke.

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