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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
Sox5, Sox6, and Sox9 are members of the Sox (sex-determining region Y-box) protein family and the High-Mobility Group (HMG) super family of DNA binding proteins, which are characterized by sequence homology to the HMG domain of the sex-determining region on the Y chromosome. Sox9 is the master regulator of chondrocyte differentiation and is coexpressed with Sox5 (as L-Sox5) and Sox6 (Akiyama et al. 2002; Akiyama 2008).
Molecular adaptations to endurance exercise and skeletal muscle fibre plasticity
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
One unique feature of MyHC isoform regulation is that their regulation is on/off or binary in contrast to many other genes where expression is regulated along a continuum. In other words, individual muscle fibres, apart from hybrid fibres, express only one MyHC isoform, while the expression of all other MyHC isoforms is almost fully switched off. This is in stark contrast to, for example, glycolytic or oxidative enzymes, which are always expressed but increase or decrease in response to endurance exercise or inactivity, respectively. A team led by Eric Olson has identified one mechanism by which the on/off regulation of MyHC isoforms is achieved. The research team discovered that the slow MyHC 1β gene harbours two regulatory microRNAs (miRNA), miR-208b and miR-499 (termed MyoMirs) in its introns (57). This means that when the MyHC 1β gene is transcribed, the two miRNAs are made at the same time. Therefore, a muscle that expresses MyHC 1β mRNA would have high levels of miR-208b and miR-499. miRNAs are post-transcriptional epigenetic regulators as described in detail in Chapter 6. When miRNAs match a target sequence on an mRNA perfectly, the bound mRNA is rapidly degraded. When the sequence does not match exactly, miR binding prevents the translation of the associated mRNA into protein. Eva van Rooij et al. discovered that miR-208b and miR-499 bind imperfectly to Sox6 mRNA. Sox6 is a transcription factor that prevents the expression of slow genes and upregulates fast genes (58). When miR-208b and miR-499 bind the Sox6 mRNA, they prevent the production of Sox6 protein and in this way increase the expression of slow muscle genes. In support of the role of decreasing Sox6 on slow gene expression, in mice where Sox6 has been knocked out, there is a 7- to 80-fold increase in the expression of slow muscle genes. Together, these data suggest that muscle fibres maintain a single phenotype through the coordinated expression of genes and miRNAs. Evolutionarily, incorporating miRNAs into the mRNA of a MyHC gene that can then decrease the production of the opposing phenotype allows binary control of muscle phenotype (Figure 9.8).
Molecular Genetics of Cleidocranial Dysplasia
Published in Fetal and Pediatric Pathology, 2021
Jamshid Motaei, Arash Salmaninejad, Ebrahim Jamali, Imaneh Khorsand, Mohammad Ahmadvand, Sasan Shabani, Farshid Karimi, Mohammad Sadegh Nazari, Golsa Ketabchi, Fatemeh Naqipour
RUNX2 gene plays an important role in osteoblast differentiation. The expression of Indian hedgehog (Ihh) in chondrocytes induces expression of RUNX2 in mesenchymal stem cells during the development of the endochondral bone. Then, Runx2, by inhibiting the differentiation of the mesenchymal stem cells into chondrocytes and adipocytes, induces them to osteoblast progenitors. In knockout mice for Ihh-/-, osteoblasts and expression of Runx2 in perichondrium are completely absent [30]. Sp7, Runx2 and canonical Wnt signaling cause osteoblast progenitors differentiation into immature osteoblasts. Expression of Sp7 is regulated by Runx2. Osteoblast progenitors have the ability to differentiate into chondrocytes that are inhibited by canonical Wnt signaling and Sp7 (27). Notch signaling inhibits Runx2 through the Hes and Hey transcriptional inhibitors, as a result, with the proliferation of mesenchymal cells, their differentiation into osteoblasts are inhibited [31]. Runx2 expression decreases during osteoblasts maturation [32]. In the process of endochondral ossification, Runx2 plays an important role in the chondrocytes maturation. Sox5, Sox6 and Sox9 control the differentiation of mesenchymal cells into immature chondrocytes [27]. Overexpression of RUNX2 in transgenic mice increased the chondrocyte maturation and endochondral bone formation. While the expression of dominant-negative Runx2 in mice inhibited chondrocyte maturation and delayed endochondral ossification [33]. Therefore, Runx2 plays an important role in the development of chondrocytes from immature chondrocytes.
Association of Exon 14 of the SOX6 Gene Sequence Variations with Response to Hydroxyurea Therapy in Patients Carrying Non Transfusion-Dependent Thalassemia
Published in Hemoglobin, 2020
Zahra Mohammadi, Reza Mohammadi, Sezaneh Haghpanah, Mohamad Moghadam, Reza Pazhoomand, Mehran Karimi
β-Thalassemia (β-thal) is caused by mutations in the β-globin locus resulting in loss or reduction of Hb A production [1]. In non transfusion-dependent thalassemia (NTDT), although patients are homozygous or compound heterozygous, the anemia is milder than in β-thal major (β-TM) [2]. The clinical manifestations could be quite variable from mild anemia with no bone abnormalities to more severe anemia with intense erythropoietic activity [3]. In β-thal patients, γ-globin expression resulting in the formation of Hb F (α2γ2) could be substituted for lack of β-globin chains [4]. Therefore, Hb F is a major modifier of the severity in β-thal [5]. Several pharmacological agents such as 5-azacytidine, butyrate and hydroxyurea (HU), have been used to stimulate Hb F synthesis in vivo [6]. Hydroxyurea, as an s phase-specific and non-DNA-hypomethylating chemotherapeutic agent, is capable factor of inducing Hb F synthesis and markedly increases the level of Hb F [7,8]. The effect of HU and other anti metabolites of Hb F synthesis pathways is mainly mediated by their cytotoxic properties [9,10]. The Hb F induction mechanism by HU is not clearly understood. Mechanisms proposed for the induction of Hb F by HU include: rapid erythroid regeneration, increased erythropoietin (EPO) production, apoptosis, nitric oxide (NO) production, increased guanylatecyclase activity and activation of the p38MAPK pathway [11–14]. However, not all β-thal patients show an identical response to HU. Some studies suggest a possible association between the patient’s genotype and variability in response to HU, association of some single nucleotide polymorphisms (SNPs) with high Hb F baseline has been reported [4]. SOX6 is a chromatin-associated protein and a member of the Sox (Sry-type HMG box) gene family and encodes transcription factors with a conserved 79 amino acids high mobility group (HMG) domain, which is involved in DNA recognition [5].