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Embryology, Anatomy, and Physiology of the Male Reproductive System
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Male: the Y chromosome short arm (Yp11) carries the sex-determining region Y gene (SRY, also known as testis determining factor).Signals differentiation of primitive sex cords to form the testis/medullary cords.The SRY and SOX9 genes are responsible for testes differentiation.
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
Sox9 can trigger the expression of its downstream targets, FGF9 and PGDS (prostaglandin D synthase) (40). Both FGF9 and PGDS promote the proliferation and differentiation of the Sertoli cells, thus promoting the masculinization of the testis (40). A shift of balance from Sox9/FGF9 to Wnt/β-catenin signaling can result in a transition from male to female in various species (44,45). In-frame missense and splicing mutations in the MAP kinase pathway gene MAP3K1 tilt the balance from the male to the female sex-determining pathway, resulting in the 46,XY disorder of sex development. These MAP3K1 mutations arbitrate this balance by enhancing the β-catenin activity and WNT/β-catenin/FOXL2 expression and by reducing the expression of SOX9/FGF9/FGFR2/SRY (46). In summary, Wnt signaling plays a major inhibitory role in testis determination.
Articular Cartilage Development
Published in Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi, Articular Cartilage, 2017
Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi
Regulation of Sox9 expression is under the control of BMP signaling, with BMP2 indicated in direct upregulation of Sox9 (Healy et al. 1999; Zehentner et al. 1999). Sox9 maintains the chondrocyte phenotype and prevents chondrocytes from undergoing terminal differentiation and hypertrophy (Figure 2.24). Loss of Sox9, Sox5, and Sox6 presages differentiation into hypertrophic chondrocytes (Lefebvre et al. 2001; Okubo and Reddi 2003). Sox9 is also directly responsible for regulating the expression of multiple extracellular matrix components that define cartilage, including aggrecan; types II, IX, and XI collagens; and COMP (Zhou et al. 1998; Liu et al. 2000; Sekiya et al. 2000; Panda et al. 2001; Zhang et al. 2003), although regulation of type II collagen by Sox9 is dependent on the state of differentiation (Aigner et al. 2003; Kypriotou et al. 2003). Also important in chondroblast differentiation is the MAPK-controlled Runx2, which becomes important for cells in entering the hypertrophic stage (Papachristou et al. 2005). These transcription factors function not only during development but also during tissue maintenance and maturation. Changes in their expression and regulation, for a variety of reasons, mediate differences in gene expression as cartilage ages.
IL-6, IL-1β and TNF-α regulation of the chondrocyte phenotype: a possible mechanism of haemophilic cartilage destruction
Published in Hematology, 2023
Liujie Zheng, Zhiwei Han, Dasheng Luo, Jiale Li, Nanyu Pang, Mingyang Ding, Houlong Ye, Keyan Zhu, Yunfeng Yao
FGF23 is a protein that is a member of FGF19 subfamily which has been widely studied in phosphate and vitamin D metabolism over the last few decades [4–6]. This secretory protein has also been confirmed to play a crucial part in regulating cartilage metabolism. Excess FGF23 has a strong inhibitory effect on chondrocyte proliferation. FGF23 overload has been shown to upregulate MMP13 expression in chondrocytes resulting in cartilage ECM degradation and subsequent cartilage destruction [7,8]. SOX9, a member of the SOX (SRY-related HMG-box) family that is mainly secreted by chondrocytes, could also be a vital regulator of the cartilage metabolic cycle [9,10]. Low levels of SOX9 in cartilage may inhibit chondrogenesis, cartilage regeneration and differentiation [11]. Additionally, down-regulated expression of SOX9 may upregulate the MMP13 expression in chondrocytes [8]. In a previous study, we found higher levels of FGF23 and lower levels of SOX9 in HA cartilage compared with osteoarthritis (OA), and showed that the expression of FGF23 and SOX9 affected iron regulation in chondrocytes [12]. Like iron, proinflammatory cytokines also have a key role in HA cartilage degradation pathogenesis, but their relationship to phenotype alterations in chondrocytes remains unclear.
The use of in silico extreme pathway (ExPa) analysis to identify conserved reproductive transcriptional-regulatory networks in humans, mice, and zebrafish
Published in Systems Biology in Reproductive Medicine, 2023
Almost all male genes from SRY to AR, to lesser or greater extents, coregulated with one another. FGF9, PGD2, DHH, DKK1, and AR appear near constitutively coactive with ExPa predicted levels of ≥33% with all male genes (Figure 3A). FGF9 and PGD2 are essential for maintaining elevated SOX9 activity in somatic cells and for perpetuating the male developmental morphogenetic program. As a decisive gene and TF, SOX9 locks-in its own irrevocable expression in partnership with FGF9 and PGD2 (Warr and Greenfield 2012; Capel 2017). The three factors, i.e., SOX9, FGF9, and PGD2 do not directly interact with one another. Instead, SOX9 acts as a TF up-regulating FGF9 production, which blocks the activation of WNT4, a TF responsible for sex differentiation to the female phenotype (Eggers and Sinclair 2012). Whereas PGD2 regulates SOX9 nuclear translocation and downstream activations of TFs involved in sex determination and differentiation (Chen et al. 2017). The signaling molecules DHH and DKK1 are essential for mediating the differentiation of male gonad somatic cells and act as inhibitors of the female WNT signaling pathway (Glinka et al. 1998; Eggers and Sinclair 2012). Finally, the constitutive AR expression supports its role as a receptor that is responsive to androgen productions from somatic cells, and for instantiating virilization during fetal, pubertal, and adult life stages of the male sexual phenotype (Rey 2020) (Figure 3A).
Circular RNA from phosphodiesterase 4D can attenuate chondrocyte apoptosis and matrix degradation under OA milieu induced by IL-1β via circPDE4D/miR-4306/SOX9 Cascade
Published in Immunopharmacology and Immunotoxicology, 2022
Lixia Gao, Xiaoyun Wang, Jian Xiong, Yan Ma
Reportedly, OA is the result of pathological action of several transcription factors [9]. Sex-determining region Y-box 9 (SOX9) is a pivotal transcription factor involved in various diseases including cancer and OA [10, 11], and SOX9 is a cartilage master regulator [12]. Successive steps in cartilage development and generation, as well as the tumorigenesis in cartilage are controlled by SOX9 via regulating downstream transcriptional targets [11]. Besides, aging is the greatest risk factor for OA, and SOX9 expression in articular cartilage is age-dependent and epigenetics-dependent [13]. Furthermore, microRNA (miRNA) is a newly defined epigenetic mechanism underlying the expression of SOX9 [13], and other noncoding RNAs including long noncoding RNA (lncRNA) and circRNA can regulate miRNAs/SOX9 interaction [14].