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Pathogenesis: Molecular mechanisms of osteoporosis
Published in Peter V. Giannoudis, Thomas A. Einhorn, Surgical and Medical Treatment of Osteoporosis, 2020
Anastasia E. Markatseli, Theodora E. Markatseli, Alexandros A. Drosos
Wnt proteins can activate three intracellular signaling pathways: (a) the planar cell polarity pathway, which plays a dominant role in embryogenesis; (b) the Wnt/Cα2+ pathway, which regulates cell migration; and (c) the canonical Wnt signaling pathway, which is involved in the bone remodeling as well as in the development and differentiation of organs in mammals (223,231–233). The canonical Wnt signaling pathway seems to play a crucial role in both osteoblast precursors and differentiated osteoblasts (227,234–238).
Breast Cancer Stem Cells and Their Niche: Lethal Seeds in Lethal Soil
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
Danuta Balicki, Brian Leyland-Jones, Max S. Wicha
The final stem cell marker in this chapter is wingless (Wnt)/β-catenin. The canonical Wnt/β-catenin signaling pathway modulates the delicate balance between stemness, differentiation, and tumorigenesis in several adult stem cell niches such as the hair follicles in the skin, the mammary gland, hematopoiesis, and the intestinal crypt (8,69). Differences in the levels of Wnt signaling activity reflect tumor heterogeneity and are likely to account for distinct cellular activities such as proliferation and epithelial-mesenchymal transitions, which prompt tumor growth and malignant behavior, respectively. This pivotal pathway is highly conserved in evolution and is known to regulate cell-fate decisions, cell proliferation, morphology, migration, apoptosis, differentiation, and stem cell self-renewal. Recent evidence which suggests that Wnt signaling plays a role in human breast cancer include the detection of elevated levels of nuclear and/or cytoplasmic β-catenin using immunohistochemistry, and the overexpression or downregulation of specific Wnt proteins. The Wnt pathway has also been implicated in normal stem cell self-renewal in vivo, and there is evidence that dysregulation of this pathway in the mammary gland and other organs may play a key role in carcinogenesis (70).
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
The Wnt signaling pathway is a highly conserved cell-to-cell communication mechanism during development (1). It has essential functions in tissue homeostasis, and dysregulation of Wnt signaling could lead to several pathological states (2). It is categorized into canonical (Wnt/β-catenin) and noncanonical branches. In this chapter, we mainly focus on the canonical pathway, which is commonly known as the Wnt/β-catenin signaling pathway (3). Wnt proteins (ligands), which are secreted cysteine-rich proteins, initiate the Wnt signaling (4). The process of spermatogenesis is regulated by various factors including the extrinsic and intrinsic regulators. Hormones and paracrine factors are extrinsic regulators, whereas intrinsic regulators are the genetic factors. Among the paracrine regulators, Wnt signaling plays a key role in germ cell development (4). There are 19 Wnt proteins secreted in vertebrates, out of which Wnt1 (5), Wnt3 (6), Wnt3a (7), Wnt4 (8), Wnt5a (9), Wnt7a (10), Wnt10b (11) and Wnt11 (12) have been identified in the developing or adult testes of male rodents or humans.
MiR-122-5p promotes peritoneal fibrosis in a rat model of peritoneal dialysis by targeting Smad5 to activate Wnt/β-catenin pathway
Published in Renal Failure, 2022
Yirong Liu, Zhihong Ma, Zhenxing Huang, Dongmei Zou, Junbin Li, Ping Feng
Wnt protein is a type of secreted lipidated glycoprotein rich in cysteine, which is involved in cell differentiation, proliferation, and migration [29]. The Wnt signaling pathway, an essential component in early development, helps control cell differentiation and polarity through at least three distinct pathways [30]. The canonical Wnt pathway acting through activation of β-catenin is the best characterized [31,32]. In recent years, the role of Wnt/β-catenin signaling pathway in regulating EMT during organ fibrosis has been established [33]. The inhibition of Wnt/β-catenin signaling pathway limited collagen abundance and suppressed the progression of renal fibrosis [34]. Particularly, the activation of Wnt/β-catenin signaling pathway plays a key role in PF. Clinically, the higher expressions of Wnt1, Wnt5a, β-catenin, and LEF1 were observed in patients with more than 1-year PD compared with patients who just started with PD [35]. It has also been reported that Wnt/β-catenin signaling pathway induces EMT in human peritoneal mesothelial cells [35,36]. Our study proved that Wnt/β-catenin signaling pathway was activated in peritoneum of PD rat. MiRNA-122-5p mimic significantly strengthened the expression of Wnt1 and β-catenin and the expression of target genes c-Jun, c-Myc, and Cyclin D1, which could be reversed by Smad5 overexpression, suggesting that miRNA-122-5p/Smad5 axis maybe induce PF through regulating the Wnt/β-catenin signaling pathway.
Endothelial to mesenchymal transition (EndMT) and vascular remodeling in pulmonary hypertension and idiopathic pulmonary fibrosis
Published in Expert Review of Respiratory Medicine, 2020
Archana Vijay Gaikwad, Mathew Suji Eapen, Kielan D. McAlinden, Collin Chia, Josie Larby, Stephen Myers, Surajit Dey, Greg Haug, James Markos, Allan R. Glanville, Sukhwinder Singh Sohal
Involvement of WNT proteins in tissue fibrosis has been observed through several recent studies. The WNT/β-catenin pathway is responsible for the activation of several profibrotic steps that promote myofibroblast differentiation through Smad-dependent autocrine TGF-β signaling, consequently, promoting fibrogenic pathogenesis [157–159]. Recently, activation of the WNT/β-catenin pathway was observed in fibroproliferative disorders of kidney and liver tissues [160]. The WNT/β-catenin pathway is strongly activated in the lung tissues of patients with IPF [161], reflecting possibilities other than TGF-β [162]. Also, recent studies using mouse cell lines showed canonical WNT signaling in cultured endothelial cells resulted in EndMT. These studies demonstrated that canonical WNT signaling activity is a characteristic property of EndMT-derived mesenchymal cells which involves cardiac tissue repair after myocardial infarction [163,164]. WNT signaling pathways have been shown to be functional in pulmonary fibrosis pathology through epithelial-mesenchymal cross-talk [165], however there is still ambiguity about WNT signaling in pulmonary fibrosis through EndMT.
Targeting the Wnt/β-catenin pathway in neurodegenerative diseases: recent approaches and current challenges
Published in Expert Opinion on Drug Discovery, 2020
Annalucia Serafino, Daniela Giovannini, Simona Rossi, Mauro Cozzolino
Wnts are secreted, cysteine-rich glycoproteins that act as ligands to locally stimulate receptor-mediated signal transduction of Wnt pathway in both vertebrates and invertebrates [2,10,27–30]. Wnt signals are transduced in the canonical, or β-catenin-dependent, pathway and in two non-canonical, or β-catenin-independent, pathways, the Wnt/Ca2+ signaling and the planar cell polarity (PCP) signaling [28–30]. The seven-pass transmembrane receptors of the Frizzled (Fzd) family are crucial for almost all Wnt signaling cascades, and the N-terminal Fzd cysteine-rich domain (CRD) acts as the Wnt binding domain [28]. In addition to the Fzd receptor, the Wnt/β-catenin pathway needs the low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) co-receptors [31]. Wnt proteins are usually enclosed in the Wnt1 (including Wnt2, Wnt3, Wnt3a, Wnt8, and Wnt8a), and the Wnt5a (including Wnt4, Wnt5a, Wnt5b, Wnt6, Wnt7a, and Wnt11) classes. While the Wnt5a class signals generally act via the β-catenin-independent ‘non-canonical’ pathways, the Wnt1-like proteins, through the binding with the Fzd receptor and the LRP5/6 co-receptors, directly activate the canonical β-catenin-dependent pathway.