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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
New candidates associated with BMD have also been suggested, including wntless Wnt ligand secretion mediator (GPR177) genes, and SRY-box 6 (SOX6), a transcriptional activator that is required for normal development of chondrogenesis and maintenance of skeletal muscle cells (73). A panel of more than 25 genes has been associated with BMD by GWAS analysis in postmenopausal women, including ARHGAP1, CLCN7, CTNNB1, ESR1, FAM3C, FLJ42280, FOXL1, GALNT3, GPR177, HDAC5, IBSP, JAG1, LRP5, LTBP3, MARK3, MEF2C, MEPE, OPG, RANK, RANKL, RSPO3, SOST, SOX4, SOX6, SP7 (Osterix), TARD3NL, and ZBTB40 (74).
Genetic Basis of Blood Pressure and Hypertension
Published in Giuseppe Mancia, Guido Grassi, Konstantinos P. Tsioufis, Anna F. Dominiczak, Enrico Agabiti Rosei, Manual of Hypertension of the European Society of Hypertension, 2019
Sandosh Padmanabhan, Alisha Aman, Anna F. Dominiczak
Advances in genomics have accelerated over the last decade, leading to an unparalleled leap in our understanding of the genetic architecture of BP and HTN (40). While the technological and analytic aspects of genomics have been very successful in discovering DNA sequence variants associated with BP and HTN, the functional and biological significance of the vast number of these variants in the human genome are unknown. The UMOD locus from GWAS is now the basis of a clinical trial (clinicaltrials.gov NCT03354897) to reposition a loop diuretic in the HTN care pathway. Other GWAS loci encoding MARK3, PDGFC, TRHR, ADORA1, GABRA2, VEGFA and PDE3A within systems that have existing drugs not currently linked to a known antihypertensive mechanism and may offer repurposing opportunities. Moving from single-locus dissection, newer analytic methods will test the molecular network hypothesis on a genome-wide scale to fully understand the networks of pathways that govern the genotype—BP causality relationship. Another emerging hypothesis for contributions from the genome to complex traits is that alterations in nuclear organization of DNA resulting in higher order structures, such as folds of DNA within chromatin, confer differential susceptibility. Other ‘omics’ technologies such as metabolomics and metagenomics are potentially powerful tools to identify molecular pathways, involvement of the microbiome and environmental factors in influencing the BP phenotype. Thus the future of BP genomics is set to move into the realms of further discovery using novel platforms, functional dissection and validation of pathways in molecular and clinical studies.
The role of microtubules in the regulation of epithelial junctions
Published in Tissue Barriers, 2018
Ekaterina Vasileva, Sandra Citi
Microtubule affinity-regulating kinases (MARKs) are an evolutionarily conserved family of kinases that comprise MARK1(PAR-1c), MARK2 (PAR-1b/EMK), MARK3 (PAR-1a/C-TAK1) and MARK4 (PAR-1d/MARKL1).152 Mammalian MARKs are homologous to the invertebrate partitioning gene product Par-1, which regulates development of cell polarity,153 and belong to the same family of energy sensing kinases as AMPK.154 MARKs are indirectly associated with MTs, since they were identified as kinases that phosphorylate the MT-regulating proteins tau and MAPs, to regulate MT dynamics and MT-dependent transport.155 There is evidence that MARK proteins are involved in different aspects of epithelial differentiation. For example, MARK4 localizes to the basal body and promotes ciliogenesis in ciliated cells,156 and MARK2 functions downstream of aPKC in the establishment and maintenance of epithelial cell polarity in mammalian cells157 (Figure 3). Importantly, MARK2 (PAR1b) has been localized both at apical and lateral epithelial junctions,157 and is required for the formation of apical lumens in epithelial cells grown in 3D, by promoting the apicobasal alignment of MTs, and by modulating myosin-II and E-cadherin dependent signaling158,159 (Figure 3). MARKs are involved in regulation of different signaling pathways, for example through the phosphorylation of proteins involved in membrane recycling,160 RhoA/Rac1 signaling,115,161,162 inflammation,163 and the Hippo pathway.164 However, although MARK2 has been localized at junctions,157,158 little is known about the junctional localization of other MARKs (MARK1, MARK3 and MARK4), the mechanisms that regulate the subcellular localizations of MARKs, and the effect of junctional localization on the enzymatic activity and signaling functions of MARK proteins.