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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
The most important pathways in osteoclastogenesis are (a) IKK/NF-κB and (b) calcineurin/NFATc1. RANK's binding to TRAF 6 results in the activation of NF-κB and its transition to the nucleus. NF-κB induces the expression of the transcription factor c-Fos. NF-κB and c-Fos interact with NFATc1 and thus promote the transcription of genes implicated in osteoclastogenesis. NFATc1 plays a significant role in the modulation of osteoclastogenesis (170). The bisphosphorylation of calcineurin is calcium dependent and also leads to the activation of NFATc1. C-Fos and RNA polymerase II contribute to the increase of the NFATc1 activation (171) (Figure 2.2b).
Soluble Mediators of Cellular Cooperation: The Cytokines
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
A failure of cytokine gene transcription may also be responsible for some cases of severe combined immunodeficiency. Figure 7–1 is a diagram of the promoter region of the IL-2 gene. It has organization and sequence elements similar to those of promoters and enhancers of immunoglobulin and T cell receptor genes (see Chapters 4 and 6). In some cases of SCID, patients appear to have a defect in production of IL-2 and/or other cytokines which is not related to actual lesions in the genes encoding them. These conditions may result from abnormal transcriptional regulation of cytokine synthesis. One patient has been described in which the NFAT-1 transcription factor appeared to be abnormal.
Analyzing the GPCR Function of Polycystin-1
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Stephen C. Parnell, Robin L. Maser, Brenda S. Magenheimer, James P. Calvet
To identify potential signaling pathways from polycystin-1 that can modulate intracellular Ca2+ mechanisms, we coexpressed various PC1 C-tail deletion constructs with an NFAT promoter-luciferase reporter construct having four composite NFAT/AP-1 binding sites from the human interleukin-2 promoter.58 NFAT is a Ca2+-regulated transcription factor. The full-length PC1 C-tail construct (PC1-LT222) was shown to be capable of producing significant activation of the NFAT reporter.21 Using the various truncated C-tail constructs established that PC1-induced NFAT activation is dependent on an intact G-protein binding and activation region, and does not require the coiled-coil region. Coexpression of Gαq or Gα12 expression vectors with the PC1 cDNA resulted in further stimulation of PC1-LT222-induced NFAT activation.
Effects of potassium channel knockdown on peripheral blood T lymphocytes and NFAT signaling pathway in Xinjiang Kazak patients with hypertension
Published in Clinical and Experimental Hypertension, 2023
Chen Dai, Meng Tan, Xiaopan Meng, Jian Dong, Yuanming Zhang
Previous studies have demonstrated that the potassium channels and nuclear factor of activated T cells (NFAT) are closely related to the T lymphocyte activation (17,18). There are two major types of membrane ion channels on T lymphocytes, namely the voltage-gated potassium channels (Kv1.3) and calcium-activated potassium channels (KCa3.1) (19). These channels help maintain membrane potential by mediating the outflow of potassium, while the altered membrane potential would indirectly affect the calcium signaling within the cells (20). Therefore, the potassium channels on T lymphocytes are closely related to the intracellular Ca2+ regulation. Calcium is an important second messenger associated with the NFAT signaling pathway. Increased Ca2+ concentration can activate the calcineurin (CaN), which triggers the T lymphocyte activation through NFAT signaling pathway (21) 1. The NFAT signaling pathway can also mediate the lymphocyte proliferation and differentiation. Furthermore, NFAT would activate the production of cytokines, including the tumor necrosis factor-α, IL-4, IL-6, and IFN-β (22). Whether the potassium channels are involved in the occurrence of inflammatory state in the body through the NFAT signaling pathway remains to be elucidated.
FAEE exerts a protective effect against osteoporosis by regulating the MAPK signalling pathway
Published in Pharmaceutical Biology, 2022
Ming‑Yue Wang, Meng‑Fei An, Mao-Si Fan, Shao-Shi Zhang, Ze‑Rui Sun, Yun‑Li Zhao, Ze-Min Xiang, Jun Sheng
Mounting evidence indicates that during osteoclastogenesis, NFATc1 is a ‘master executor’ of RANKL-induced osteoclast differentiation/activation (Takayanagi 2007a; Sakai et al. 2016). Stimulation of RAW 264.7 cells by RANKL increases NFATc1 expression (Wang et al. 2018). NFATc1 is also a downstream nuclear transcription factor that plays a vital part in regulating expression of the osteoclast-specific genes, TRAP, cathepsin K, MMP-9, c-Src, OSCAR and ATP6v0d2 (Takayanagi 2007a, 2007b; Chen et al. 2014), which are related to regulation of the differentiation, fusion and activation of osteoclasts. We showed that FAEE suppressed the RANKL-mediated stimulation of expression of NFATc1 mRNA and protein, and concurrently inhibited mRNA expression of NFATc1-mediated osteoclastogenic genes.
A polypeptide inhibitor of calcineurin blocks the calcineurin-NFAT signalling pathway in vivo and in vitro
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Ping Wang, Wenying Li, Yumeng Yang, Na Cheng, Yuchen Zhang, Nan Zhang, Yanxia Yin, Li Tong, Zhimei Li, Jing Luo
Calcineurin (CN) is a serine/threonine protein phosphatase. It is widely distributed in various tissues, especially in nerve tissues and lymphocytes1,2. CN is a heterodimer composed of the catalytic subunit CNA and the regulatory subunit CNB. Its activity is regulated by Ca2+ and calmodulin (CaM). CN has a variety of substrates and plays an important role in various processes, including the immune response, autophagy and other biological systems3. T cell activating transcription factor (NFAT) is one of the substrates of CN. NFAT plays an important role in the development, activation and function of the immune system. In addition to T cells, NFAT is also expressed in a variety of other immune cells, regulating the expression of a variety of cytokines, such as IL-2, IL-3 and TNF α4.