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Definition, risk factors, and epidemiology of osteoporosis
Published in Peter V. Giannoudis, Thomas A. Einhorn, Surgical and Medical Treatment of Osteoporosis, 2020
The Wnt pathways enhance the osteoblast differentiation of bone marrow mesenchymal stem cells (MSCs) and the proliferation and differentiation of osteoblast progenitors by binding the Wnt ligand to its membrane receptor complex. The receptor is a complex of specific Frizzled (FZD) proteins and the low-density lipoprotein receptor-related protein 5/6 (LRP-5/6). Activated membrane ligand-receptor complexes release and stabilize β-catenin (OPG inhibitor) as intracellular signaling to regulate the Runx2 and Osterix gene coding proteins at the nuclei level, together with transcription factor 4 (TCF-4) or lymphoid enhancer binding factor 1 (LEF-1). Wnt signaling also reduces bone resorption by the competitive binding of secreted Frizzled-related protein 1 (Sfrp1) to RANKL expressed in osteoclast activity. Other regulators of this pathway include insulin-like growth factor 1 (IGF-1), Notch, and Sclerostin. BMPs are cytokines belonging to the transforming growth factor-beta (TGF-β) superfamily, which stimulates the phosphorylation of R-Smads (Samd1, Smad5, and Smad8), which, in turn, form complexes with Co-Smad (Smad4) modulating gene expression at the nuclei level, and thus increase osteogenesis. In this pathway, Runx2 regulates the gene expression of osteopontin (OPN), bone sialoprotein (BSP), osteocalcin (OCN), and PI3K/Akt and the activation of Smads.
Wnt signaling in spermatogenesis and male infertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Vertika Singh, Meghali Joshi, Kiran Singh, Rajender Singh
Canonical Wnt signaling involves the accumulation of β-catenin in the cytoplasm and its subsequent translocation into the nucleus (Figure 9.1). When there is no ligand, a destruction complex is formed, which consists of a group of proteins, mainly Axin, adenomatous polyposis coli (APC), casein kinase 1α (CK1α) and glycogen synthase kinase 3 (GSK-3). β-Vatenin is phosphorylated by casein kinase 1α (CK1α) at Ser45, followed by phosphorylation by GSK-3 at Thr41, Ser37 and Ser33. Phosphorylated β-catenin becomes ubiquitylated and is targeted for proteasomal degradation (20). On binding of Wnt to a receptor complex, which is composed of members of the Frizzled (Fz) family of seven-transmembrane, low-density lipoprotein receptor-related protein (LRP), serpentine receptors, the Axin-APC-CK1α-GSK-3 complex is inhibited. This inhibition stops phosphorylation of β-catenin by CK1α and GSK-3, further inhibiting its proteasomal degradation. This unphosphorylated β-catenin accumulates in the cytoplasm and is translocated into the nucleus where it interacts with the T-cell-specific transcription factor/lymphoid enhancer-binding factor 1 (TCF/LEF) family of transcription factors and regulates the expression of the target genes (21).
Lef1 is transcriptionally activated by Klf4 and suppresses hyperoxia-induced alveolar epithelial cell injury
Published in Experimental Lung Research, 2022
Min Yang, Xueshan Huang, Fang Shen, Juanjuan Yi, Yanni Meng, Yanping Chen
Lymphoid enhancer-binding factor 1 (LEF1) is a transcription factor that belongs to the family of T cell factor.8 As a transcription factor, Lef1 participates in the typical Wnt/β-catenin pathway.9,10 Meanwhile, LEF1 has been linked to the occurrence and development of a variety of diseases.11,12 Researches have demonstrated that Lef1 can enhance B cell proliferation13 as well as differentiation.14 Cai et al.15 found that LEF1 expression declines with increasing BPD severity, and in that case, LEF1 is adversely linked with BPD development. In a recent work, we discovered that the expression of LEF1 in the blood of BPD preterm newborns reduced as the severity of the condition increased.16 However, the role and mechanism of LEF1 in BPD remain unknown.
The Wnt/β-catenin pathway in breast cancer therapy: a pre-clinical perspective of its targeting for clinical translation
Published in Expert Review of Anticancer Therapy, 2022
Dezaree Raut, Amisha Vora, Lokesh Kumar Bhatt
Wnt/β-catenin signaling pathway has its role in morphogenesis, development, proliferation, and differentiation regulation [16]. In addition, it is involved in the homeostasis of tissue and development during the embryonic stage [15]. In the absence of Wnt, phosphorylation of β-catenin occurs because of APC, Axin, and GSK-3β, which further cause ubiquitination and proteasome-mediated degradation [15]. There is always proteasome-mediated degradation due to which the cytoplasmic level of β-catenin is kept low. This degradation is controlled by glycogen synthase kinase-3β (GSK-3β), adenomatous polyposis coli (APC), and Axin (GSK-3β/APC/Axin) [15,17]. When Wnt proteins bind to Frizzled (Fz)/Low-density related lipoprotein (LRP) complex on the cell surface, the receptors transfer the signal to intracellular proteins like GSK-3β, Dvl, APC, and Axin. Here, a heteromeric complex is formed by Dvl with Axin [15,17]. In the presence of Wnt, β-catenin accumulation occurs as the APC/Axin/GSK-3β degradation complex cannot phosphorylate β-catenin. Since β-catenin is a transcription regulator, the accumulation of this protein triggers the transcription of Wnt-specific genes (Figure 1)[15]. A T cell-specific transcription factor/lymphoid enhancer-binding factor 1 (TCF/LEF) is present in the nucleus. β-catenin present in the nucleus interacts with this TCF/LEF to cause transcription [18].
Effect of Porphyromonas gingivalis infection in the placenta and umbilical cord in pregnant mice with low birth weight
Published in Acta Odontologica Scandinavica, 2018
Sayuri Udagawa, Sayaka Katagiri, Shogo Maekawa, Yasuo Takeuchi, Rina Komazaki, Anri Ohtsu, Naoki Sasaki, Takahiko Shiba, Kazuki Watanabe, Kazuyuki Ishihara, Noriko Sato, Naoyuki Miyasaka, Yuichi Izumi
In this study, we performed a microarray analysis to assess the comprehensive gene expression profile in the umbilical cord, and the mRNA expression of several genes was validated by quantitative PCR. We found that several genes, including Orm1, Mgl2, Rps6ka3 and Trim15, were upregulated in mice that received daily P. gingivalis injections. The Orm1 gene encodes an ORM protein, also known as α-1-acid glycoprotein, which is a highly glycosylated polyanionic protein [39]. ORM is an abundant plasma protein induced under stress such as tissue injury, inflammation and infections [40], and has a protection role in animals following lethal shock induced by TNF or LPS [41]. MGL2, encoded by the Mgl2 gene, is a known marker of M2 macrophages. There are two well-established polarized phenotypes of macrophages: M1 macrophages as classically activated macrophages and M2 macrophages as alternatively activated macrophages [42]. In contrast to M1 macrophages, M2 macrophages play a role in polarization Th2-type immune responses, parasite clearance, resolution of or smoldering inflammation, tissue remodeling, angiogenesis, tumor progression and immunoregulation [43]. Sarr et al. [44] revealed that infection induced macrophage accumulation in the junctional zone of the placenta. P. gingivalis infection causes inflammation in the placenta and the proportion of M2 macrophages may be increased in the umbilical cord. Rps6ka3 encodes the ribosomal S6 kinase (RSK) protein [45], which promotes the mammalian target of rapamycin complex-1 (mTORC1) signaling pathway [46]. The mTOR pathway regulates various major cellular processes such as cell proliferation, differentiation and cell survival [47] and is activated in pathological conditions. Lef1 encodes the lymphoid enhancer-binding factor 1 (LEF-1) protein, a 54-kDa nuclear protein that is expressed specifically in pre-B and T cells [48]. LEF1 is a central regulator of iNKT cells, which are innate-like T cells that rapidly produce cytokines for antimicrobial immune responses [49]. Increased mRNA expression of Orm1, Mgl2 and Rps6ka3 in the umbilical cord suggests that bacteremia induced inflammation in the umbilical cord of mice in the ED group. Although not statistically significant, we observed an increased trend of Lef1 mRNA expression in the ED group, which might suggest that iNKT cells accumulated in the umbilical cord in response to P. gingivalis infection. Therefore, the umbilical cord may have a role in protecting fetuses from infection.