Pharmacologic epigenetic modulators of alkaline phosphatase in chronic kidney disease

Mathias Haarhaus, Dean Gilham, Ewelina Kulikowski, Per Magnusson, Kamyar Kalantar-Zadeh, Mathias Haarhaus, Dean Gilham, Ewelina Kulikowski, Per Magnusson, Kamyar Kalantar-Zadeh

Abstract

Purpose of review: In chronic kidney disease (CKD), disturbance of several metabolic regulatory mechanisms cause premature ageing, accelerated cardiovascular disease (CVD), and mortality. Single-target interventions have repeatedly failed to improve the prognosis for CKD patients. Epigenetic interventions have the potential to modulate several pathogenetic processes simultaneously. Alkaline phosphatase (ALP) is a robust predictor of CVD and all-cause mortality and implicated in pathogenic processes associated with CVD in CKD.

Recent findings: In experimental studies, epigenetic modulation of ALP by microRNAs or bromodomain and extraterminal (BET) protein inhibition has shown promising results for the treatment of CVD and other chronic metabolic diseases. The BET inhibitor apabetalone is currently being evaluated for cardiovascular risk reduction in a phase III clinical study in high-risk CVD patients, including patients with CKD (ClinicalTrials.gov Identifier: NCT02586155). Phase II studies demonstrate an ALP-lowering potential of apabetalone, which was associated with improved cardiovascular and renal outcomes.

Summary: ALP is a predictor of CVD and mortality in CKD. Epigenetic modulation of ALP has the potential to affect several pathogenetic processes in CKD and thereby improve cardiovascular outcome.

Figures

FIGURE 1
FIGURE 1
Alkaline phosphatase is ubiquitously expressed; however, the contribution of alkaline phosphatase from different tissues to the circulating alkaline phosphatase activity may vary. Under healthy conditions, liver and bone isoforms of tissue-nonspecific isozyme alkaline phosphatase comprise approximately 50% each of the total circulating alkaline phosphatase activity. Intestine alkaline phosphatase can comprise up to 10% of the circulating alkaline phosphatase activity in individuals with blood group B or 0, but less than 3% in individuals with blood group A. Circulating alkaline phosphatase predicts disease-related outcomes, for example cardiovascular disease or mortality, but to which extend alkaline phosphatase derived from specific tissues contributes to the total circulating alkaline phosphatase activity in pathologic conditions remains largely undetermined. Designed by Macrovector and Brgfx - Freepik.com.
Box 1
Box 1
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FIGURE 2
FIGURE 2
Summary of mechanisms linking dephosphorylation by alkaline phosphatase to normal and pathophysiological processes. LPS, lipopolysaccharides; MMP, metalloproteinase; OPN, osteopontin; Pi, phosphate; PL, pyridoxal; PLP, pyridoxalphosphate; PPi, pyrophosphate.
FIGURE 3
FIGURE 3
Chromatin is comprised of DNA and proteins that generate a compact structure critical for packaging and stability of eukaryotic chromosomes. The primary protein components are histones, around which the DNA is wound to form a nucleosome. Epigenetics involves covalent modifications to chromatin that does not affect the underlying DNA sequence. Covalent modifications to chromatin impact both chromatin structure and recruitment of transcription complexes that, in effect, switch genes on or off. These dynamic epigenetic modifications are carried out by adding (writing) and removing (erasing) posttranslational modifications, followed by ‘reading’, which dictates gene expression and eventual phenotypic response.
FIGURE 4
FIGURE 4
Chromatin acetylation is an epigenetic modification associated with open chromatin structure and active transcription. Bromodomain and extraterminal proteins are ‘chromatin readers’ that bind acetylated lysine on histones or transcription factors via two tandem bromodomains 1 and 2 and recruit transcriptional machinery (e.g. positive transcription elongation factor and RNA polymerase II) to drive expression of bromodomain and extraterminal sensitive genes. Apabetalone is an orally available small molecule inhibitor of bromodomain and extraterminal bromodomains that causes bromodomain and extraterminal protein release from chromatin and, as a consequence, downregulation of bromodomain and extraterminal sensitive gene transcription. Apabetalone preferentially targets bromodomain 2 (represented by yellow halo), a characteristic that differentiates it from pan-bromodomain and extraterminal inhibitors that bind bromodomains 1 and 2 with equal affinity.

References

    1. Stenvinkel P, Larsson TE. Chronic kidney disease: a clinical model of premature aging. Am J Kidney Dis 2013; 62:339–351..
    1. Kooman JP, Kotanko P, Schols AM, et al. Chronic kidney disease and premature ageing. Nat Rev Nephrol 2014; 10:732–742..
    1. Wasiak S, Tsujikawa LM, Halliday C, et al. Benefit of apabetalone on plasma proteins in renal disease. Kidney Int Rep 2018; 3:711–721..
    1. Millan J. Mammalian alkaline phosphatase: from biology to applications in medicine and biotechnology. Weinheim: Wiley; 2006.
    1. Buchet R, Millan JL, Magne D. Multisystemic functions of alkaline phosphatases. Methods Mol Biol 2013; 1053:27–51..
    1. Anh DJ, Eden A, Farley JR. Quantitation of soluble and skeletal alkaline phosphatase, and insoluble alkaline phosphatase anchor-hydrolase activities in human serum. Clin Chim Acta 2001; 311:137–148..
    1. Anh DJ, Dimai HP, Hall SL, Farley JR. Skeletal alkaline phosphatase activity is primarily released from human osteoblasts in an insoluble form, and the net release is inhibited by calcium and skeletal growth factors. Calcif Tissue Int 1998; 62:332–340..
    1. Magnusson P, Sharp CA, Farley JR. Different distributions of human bone alkaline phosphatase isoforms in serum and bone tissue extracts. Clin Chim Acta 2002; 325:59–70..
    1. Haarhaus M, Brandenburg V, Kalantar-Zadeh K, et al. Alkaline phosphatase: a novel treatment target for cardiovascular disease in CKD. Nat Rev Nephrol 2017; 13:429–442..

    2. A comprehensive discussion of the link between serum alkaline phosphatase (ALP), mortality and cardiovascular disease (CVD) in chronic kidney disease and the general population.

    1. Sardiwal S, Magnusson P, Goldsmith DJ, Lamb EJ. Bone alkaline phosphatase in CKD-mineral bone disorder. Am J Kidney Dis 2013; 62:810–822..
    1. Schuetze KB, McKinsey TA. TNAP: a new player in cardiac fibrosis? Focus on ‘Tissue-nonspecific alkaline phosphatase as a target of sFRP2 in cardiac fibroblasts’. Am J Physiol Cell Physiol 2015; 309:C137–C138..
    1. Gan XT, Taniai S, Zhao G, et al. CD73-TNAP crosstalk regulates the hypertrophic response and cardiomyocyte calcification due to alpha1 adrenoceptor activation. Mol Cell Biochem 2014; 394:237–246..
    1. Whyte MP, Simmons JH, Moseley S, et al. Asfotase alfa for infants and young children with hypophosphatasia: 7 year outcomes of a single-arm, open-label, phase 2 extension trial. Lancet Diabetes Endocrinol 2019; 7:93–105..
    1. Sheen CR, Kuss P, Narisawa S, et al. Pathophysiological role of vascular smooth muscle alkaline phosphatase in medial artery calcification. J Bone Miner Res 2015; 30:824–836..
    1. Haarhaus M, Arnqvist HJ, Magnusson P. Calcifying human aortic smooth muscle cells express different bone alkaline phosphatase isoforms, including the novel B1x isoform. J Vasc Res 2013; 50:167–174..
    1. Millan JL. The role of phosphatases in the initiation of skeletal mineralization. Calcif Tissue Int 2013; 93:299–306..
    1. Halling Linder C, Ek-Rylander B, Krumpel M, et al. Bone alkaline phosphatase and tartrate-resistant acid phosphatase: potential co-regulators of bone mineralization. Calcif Tissue Int 2017; 101:92–101..
    1. Uhlin F, Fernstrom A, Knapen MHJ, et al. Long-term follow-up of biomarkers of vascular calcification after switch from traditional hemodialysis to online hemodiafiltration. Scand J Clin Lab Invest 2019; 79:174–181..
    1. Back M, Aranyi T, Cancela ML, et al. Endogenous calcification inhibitors in the prevention of vascular calcification: a consensus statement from the COST action EuroSoftCalcNet. Front Cardiovasc Med 2018; 5:196.
    1. Schurgers LJ, Spronk HM, Skepper JN, et al. Posttranslational modifications regulate matrix Gla protein function: importance for inhibition of vascular smooth muscle cell calcification. J Thromb Haemost 2007; 5:2503–2511..
    1. O’Young J, Liao Y, Xiao Y, et al. Matrix Gla protein inhibits ectopic calcification by a direct interaction with hydroxyapatite crystals. J Am Chem Soc 2011; 133:18406–18412..
    1. Nigwekar SU. Calciphylaxis. Curr Opin Nephrol Hypertens 2017; 26:276–281..
    1. Schurgers LJ, Teunissen KJ, Knapen MH, et al. Novel conformation-specific antibodies against matrix gamma-carboxyglutamic acid (Gla) protein: undercarboxylated matrix Gla protein as marker for vascular calcification. Arterioscler Thromb Vasc Biol 2005; 25:1629–1633..
    1. Schlieper G, Westenfeld R, Kruger T, et al. Circulating nonphosphorylated carboxylated matrix gla protein predicts survival in ESRD. J Am Soc Nephrol 2011; 22:387–395..
    1. Lin H, Angeli M, Chung KJ, et al. sFRP2 activates Wnt/beta-catenin signaling in cardiac fibroblasts: differential roles in cell growth, energy metabolism, and extracellular matrix remodeling. Am J Physiol Cell Physiol 2016; 311:C710–C719..
    1. Martin S, Lin H, Ejimadu C, Lee T. Tissue-nonspecific alkaline phosphatase as a target of sFRP2 in cardiac fibroblasts. Am J Physiol Cell Physiol 2015; 309:C139–C147..
    1. Koyama-Nakamura M, Mizobuchi M, Kaneko K, et al. Myocardial SPECT images in incident hemodialysis patients without ischemic heart disease. Ther Apher Dial 2015; 19:575–581..
    1. Nasri H, Baradaran A. Close association between parathyroid hormone and left ventricular function and structure in end-stage renal failure patients under maintenance hemodialysis. Bratisl Lek Listy 2004; 105:368–373..
    1. Ortega O, Rodriguez I, Hinostroza J, et al. Serum alkaline phosphatase levels and left ventricular diastolic dysfunction in patients with advanced chronic kidney disease. Nephron Extra 2011; 1:283–291..
    1. Capelli A, Lusuardi M, Cerutti CG, Donner CF. Lung alkaline phosphatase as a marker of fibrosis in chronic interstitial disorders. Am J Respir Crit Care Med 1997; 155:249–253..
    1. Pike AF, Kramer NI, Blaauboer BJ, et al. A novel hypothesis for an alkaline phosphatase ‘rescue’ mechanism in the hepatic acute phase immune response. Biochim Biophys Acta 2013; 1832:2044–2056..
    1. Lalles JP. Intestinal alkaline phosphatase: novel functions and protective effects. Nutr Rev 2014; 72:82–94..
    1. Cho IJ, Choi KH, Oh CH, et al. Effects of C-reactive protein on bone cells. Life Sci 2016; 145:1–8..
    1. Huang RL, Yuan Y, Tu J, et al. Opposing TNF-alpha/IL-1beta- and BMP-2-activated MAPK signaling pathways converge on Runx2 to regulate BMP-2-induced osteoblastic differentiation. Cell Death Dis 2014; 5:e1187.
    1. Filipowicz R, Greene T, Wei G, et al. Associations of serum skeletal alkaline phosphatase with elevated C-reactive protein and mortality. Clin J Am Soc Nephrol 2013; 8:26–32..
    1. Lee HL, Woo KM, Ryoo HM, Baek JH. Tumor necrosis factor-alpha increases alkaline phosphatase expression in vascular smooth muscle cells via MSX2 induction. Biochem Biophys Res Commun 2010; 391:1087–1092..
    1. Ding J, Ghali O, Lencel P, et al. TNF-alpha and IL-1beta inhibit RUNX2 and collagen expression but increase alkaline phosphatase activity and mineralization in human mesenchymal stem cells. Life Sci 2009; 84:499–504..
    1. Viaene L, Behets GJ, Heye S, et al. Inflammation and the bone-vascular axis in end-stage renal disease. Osteoporos Int 2016; 27:489–497..
    1. Rader BA. Alkaline phosphatase, an unconventional immune protein. Front Immunol 2017; 8:897.
    1. Tsirpanlis G. Is inflammation the link between atherosclerosis and vascular calcification in chronic kidney disease? Blood Purif 2007; 25:179–182..
    1. Shanmugham LN, Petrarca C, Castellani ML, et al. IL-1beta induces alkaline phosphatase in human phagocytes. Arch Med Res 2007; 38:39–44..
    1. Shioi A, Katagi M, Okuno Y, et al. Induction of bone-type alkaline phosphatase in human vascular smooth muscle cells: roles of tumor necrosis factor-alpha and oncostatin M derived from macrophages. Circ Res 2002; 91:9–16..
    1. Collin J, Gossl M, Matsuo Y, et al. Osteogenic monocytes within the coronary circulation and their association with plaque vulnerability in patients with early atherosclerosis. Int J Cardiol 2015; 181:57–64..
    1. Poston JT, Koyner JL. Sepsis associated acute kidney injury. BMJ 2019; 364:k4891.
    1. Hwang SD, Kim SH, Kim YO, et al. Serum alkaline phosphatase levels predict infection-related mortality and hospitalization in peritoneal dialysis patients. PLoS One 2016; 11:e0157361.
    1. Sasaki S, Hasegawa T, Kawarazaki H, et al. Development and validation of a clinical prediction rule for bacteremia among maintenance hemodialysis patients in outpatient settings. PLoS One 2017; 12:e0169975.
    1. Bates JM, Akerlund J, Mittge E, Guillemin K. Intestinal alkaline phosphatase detoxifies lipopolysaccharide and prevents inflammation in zebrafish in response to the gut microbiota. Cell Host Microbe 2007; 2:371–382..
    1. Campbell EL, MacManus CF, Kominsky DJ, et al. Resolvin E1-induced intestinal alkaline phosphatase promotes resolution of inflammation through LPS detoxification. Proc Natl Acad Sci U S A 2010; 107:14298–14303..
    1. Pickkers P, Mehta RL, Murray PT, et al. Effect of human recombinant alkaline phosphatase on 7-day creatinine clearance in patients with sepsis-associated acute kidney injury: a randomized clinical trial. JAMA 2018; 320:1998–2009..
    1. Lassenius MI, Fogarty CL, Blaut M, et al. Intestinal alkaline phosphatase at the crossroad of intestinal health and disease – a putative role in type 1 diabetes. J Intern Med 2017; 281:586–600..
    1. Yang X, Li Y, Li Y, et al. Oxidative stress-mediated atherosclerosis: mechanisms and therapies. Front Physiol 2017; 8:600.
    1. Mody N, Parhami F, Sarafian T, Demer L. Oxidative stress modulates osteoblastic differentiation of vascular and bone cells. Free Radic Biol Med 2001; 31:509–519..
    1. Cervellati C, Bonaccorsi G, Cremonini E, et al. Oxidative stress and bone resorption interplay as a possible trigger for postmenopausal osteoporosis. Biomed Res Int 2014; 2014:569563.
    1. Wilund KR, Tomayko EJ, Wu PT, et al. Intradialytic exercise training reduces oxidative stress and epicardial fat: a pilot study. Nephrol Dial Transplant 2010; 25:2695–2701..
    1. Jackson EK, Zhang Y, Cheng D. Alkaline phosphatase inhibitors attenuate renovascular responses to norepinephrine. Hypertension 2017; 69:484–493..
    1. Perticone F, Perticone M, Maio R, et al. Serum alkaline phosphatase negatively affects endothelium-dependent vasodilation in naive hypertensive patients. Hypertension 2015; 66:874–880..
    1. Manghat P, Souleimanova I, Cheung J, et al. Association of bone turnover markers and arterial stiffness in predialysis chronic kidney disease (CKD). Bone 2011; 48:1127–1132..
    1. Sigrist M, Taal M, Bungay P, McIntyre C. Progressive vascular calcification over 2 years is associated with arterial stiffening and increased mortality in patients with stages 4 and 5 chronic kidney disease. Clin J Am Soc Nephrol 2007; 2:1241–1248..
    1. Jiang L, Zhang J, Monticone RE, et al. Calpain-1 regulation of matrix metalloproteinase 2 activity in vascular smooth muscle cells facilitates age-associated aortic wall calcification and fibrosis. Hypertension 2012; 60:1192–1199..
    1. Brown WR, Thore CR. Review: cerebral microvascular pathology in ageing and neurodegeneration. Neuropathol Appl Neurobiol 2011; 37:56–74..
    1. Vasantharekha R, Priyanka HP, Swarnalingam T, et al. Interrelationship between Mini-Mental State Examination scores and biochemical parameters in patients with mild cognitive impairment and Alzheimer's disease. Geriatr Gerontol Int 2017; 17:1737–1745..
    1. Kellett KA, Williams J, Vardy ER, et al. Plasma alkaline phosphatase is elevated in Alzheimer's disease and inversely correlates with cognitive function. Int J Mol Epidemiol Genet 2011; 2:114–121..
    1. Kellett KA, Hooper NM. The role of tissue nonspecific alkaline phosphatase (TNAP) in neurodegenerative diseases: Alzheimer's disease in the focus. Subcell Biochem 2015; 76:363–374..
    1. Ryu WS, Lee SH, Kim CK, et al. High serum alkaline phosphatase in relation to cerebral small vessel disease. Atherosclerosis 2014; 232:313–318..
    1. Coburn SP. Vitamin B-6 metabolism and interactions with TNAP. Subcell Biochem 2015; 76:207–238..
    1. Chou FF, Chen JB, Hsieh KC, Liou CW. Cognitive changes after parathyroidectomy in patients with secondary hyperparathyroidism. Surgery 2008; 143:526–532..
    1. Haarhaus M, Fernstrom A, Magnusson M, Magnusson P. Clinical significance of bone alkaline phosphatase isoforms, including the novel B1x isoform, in mild to moderate chronic kidney disease. Nephrol Dial Transplant 2009; 24:3382–3389..
    1. Haarhaus M, Monier-Faugere MC, Magnusson P, Malluche HH. Bone alkaline phosphatase isoforms in hemodialysis patients with low versus nonlow bone turnover: a diagnostic test study. Am J Kidney Dis 2015; 66:99–105..
    1. Iimori S, Mori Y, Akita W, et al. Diagnostic usefulness of bone mineral density and biochemical markers of bone turnover in predicting fracture in CKD stage 5D patients-a single-center cohort study. Nephrol Dial Transplant 2012; 27:345–351..
    1. Drechsler C, Verduijn M, Pilz S, et al. Bone alkaline phosphatase and mortality in dialysis patients. Clin J Am Soc Nephrol 2011; 6:1752–1759..
    1. Yan J, Li L, Zhang M, et al. Circulating bone-specific alkaline phosphatase and abdominal aortic calcification in maintenance hemodialysis patients. Biomark Med 2018; 12:1231–1239..
    1. Swallow DM, Povey S, Parkar M, et al. Mapping of the gene coding for the human liver/bone/kidney isozyme of alkaline phosphatase to chromosome 1. Ann Hum Genet 1986; 50:229–235..
    1. Smith M, Weiss MJ, Griffin CA, et al. Regional assignment of the gene for human liver/bone/kidney alkaline phosphatase to chromosome 1p36.1-p34. Genomics 1988; 2:139–143..
    1. Weiss MJ, Ray K, Henthorn PS, et al. Structure of the human liver/bone/kidney alkaline phosphatase gene. J Biol Chem 1988; 263:12002–12010..
    1. Matsuura S, Kishi F, Kajii T. Characterization of a 5′-flanking region of the human liver/bone/kidney alkaline phosphatase gene: two kinds of mRNA from a single gene. Biochem Biophys Res Commun 1990; 168:993–1000..
    1. Studer M, Terao M, Gianni M, Garattini E. Characterization of a second promoter for the mouse liver/bone/kidney-type alkaline phosphatase gene: cell and tissue specific expression. Biochem Biophys Res Commun 1991; 179:1352–1360..
    1. Lian JB, Stein GS, van Wijnen AJ, et al. MicroRNA control of bone formation and homeostasis. Nat Rev Endocrinol 2012; 8:212–227..
    1. Otto F, Thornell AP, Crompton T, et al. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 1997; 89:765–771..
    1. Nakashima K, Zhou X, Kunkel G, et al. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 2002; 108:17–29..
    1. Komori T. Regulation of proliferation, differentiation and functions of osteoblasts by Runx2. Int J Mol Sci 2019; 20:1694.
    1. Shirakabe K, Terasawa K, Miyama K, et al. Regulation of the activity of the transcription factor Runx2 by two homeobox proteins, Msx2 and Dlx5. Genes Cells 2001; 6:851–856..
    1. Hassan MQ, Tare RS, Lee SH, et al. BMP2 commitment to the osteogenic lineage involves activation of Runx2 by DLX3 and a homeodomain transcriptional network. J Biol Chem 2006; 281:40515–40526..
    1. Zhang J, Zhang W, Dai J, et al. Overexpression of Dlx2 enhances osteogenic differentiation of BMSCs and MC3T3-E1 cells via direct upregulation of Osteocalcin and Alp. Int J Oral Sci 2019; 11:12.
    1. Waddington CH. The epigenotype. 1942. Int J Epidemiol 2012; 41:10–13..
    1. Feinberg AP. The key role of epigenetics in human disease prevention and mitigation. N Engl J Med 2018; 378:1323–1334..

    2. Important discussion of the therapeutic potential of epigenetic modulation.

    1. Pfister SX, Ashworth A. Marked for death: targeting epigenetic changes in cancer. Nat Rev Drug Discov 2017; 16:241–263..
    1. Raghuraman S, Donkin I, Versteyhe S, et al. The emerging role of epigenetics in inflammation and immunometabolism. Trends Endocrinol Metab 2016; 27:782–795..
    1. Cochran AG, Conery AR, Sims RJ., 3rd Bromodomains: a new target class for drug development. Nat Rev Drug Discov 2019; 18:609–628..

    2. Comprehensive summary of the evidence for bromodomain and extraterminal (BET) proteins as novel therapeutic targets for epigenetic therapy.

    1. Cho HH, Park HT, Kim YJ, et al. Induction of osteogenic differentiation of human mesenchymal stem cells by histone deacetylase inhibitors. J Cell Biochem 2005; 96:533–542..
    1. Li SJ, Kao YH, Chung CC, et al. HDAC I inhibitor regulates RUNX2 transactivation through canonical and noncanonical Wnt signaling in aortic valvular interstitial cells. Am J Transl Res 2019; 11:744–754..
    1. Escalante-Alcalde D, Recillas-Targa F, Hernandez-Garcia D, et al. Retinoic acid and methylation cis-regulatory elements control the mouse tissue nonspecific alkaline phosphatase gene expression. Mech Dev 1996; 57:21–32..
    1. Delgado-Calle J, Sanudo C, Sanchez-Verde L, et al. Epigenetic regulation of alkaline phosphatase in human cells of the osteoblastic lineage. Bone 2011; 49:830–838..
    1. Ha SW, Jang HL, Nam KT, Beck GR., Jr Nano-hydroxyapatite modulates osteoblast lineage commitment by stimulation of DNA methylation and regulation of gene expression. Biomaterials 2015; 65:32–42..
    1. Montes de Oca A, Madueño J, Martinez J, et al. High phosphate-induced calcification is related to SM22alpha promoter methylation in vascular smooth muscle cells. J Bone Miner Res 2010; 25:1996–2005..
    1. van Meurs JB, Boer CG, Lopez-Delgado L, Riancho JA. Role of epigenomics in bone and cartilage disease. J Bone Miner Res 2019; 34:215–230..

    2. The article discusses the relevance of epigenomics for the pathogenesis of bone diseases.

    1. Taipaleenmaki H. Regulation of bone metabolism by microRNAs. Curr Osteoporos Rep 2018; 16:1–12..
    1. Hackl M, Heilmeier U, Weilner S, Grillari J. Circulating microRNAs as novel biomarkers for bone diseases – complex signatures for multifactorial diseases? Mol Cell Endocrinol 2016; 432:83–95..
    1. Makitie RE, Hackl M, Niinimaki R, et al. Altered MicroRNA profile in osteoporosis caused by impaired WNT signaling. J Clin Endocrinol Metab 2018; 103:1985–1996..
    1. Chen Q, Liu W, Sinha KM, et al. Identification and characterization of microRNAs controlled by the osteoblast-specific transcription factor Osterix. PLoS One 2013; 8:e58104.
    1. Feng Q, Zheng S, Zheng J. The emerging role of microRNAs in bone remodeling and its therapeutic implications for osteoporosis. Biosci Rep 2018; 38:BSR20180453.

    2. Discussion of the role of microRNAs (miRNAs) in bone physiology and in skelettal disordes, including implications for therapeutic use.

    1. Du F, Wu H, Zhou Z, Liu YU. microRNA-375 inhibits osteogenic differentiation by targeting runt-related transcription factor 2. Exp Ther Med 2015; 10:207–212..
    1. Zhang W, Wu Y, Shiozaki Y, et al. miRNA-133a-5p inhibits the expression of osteoblast differentiation-associated markers by targeting the 3′ UTR of RUNX2. DNA Cell Biol 2018; 37:199–209..
    1. Li H, Li T, Fan J, et al. miR-216a rescues dexamethasone suppression of osteogenesis, promotes osteoblast differentiation and enhances bone formation, by regulating c-Cbl-mediated PI3K/AKT pathway. Cell Death Differ 2015; 22:1935–1945..
    1. Metzinger-Le Meuth V, Burtey S, Maitrias P, et al. microRNAs in the pathophysiology of CKD–MBD: biomarkers and innovative drugs. Biochim Biophys Acta Mol Basis Dis 2017; 1863:337–345..
    1. Kozomara A, Birgaoanu M, Griffiths-Jones S. miRBase: from microRNA sequences to function. Nucleic Acids Res 2019; 47:D155–D162..
    1. Fakhry M, Skafi N, Fayyad-Kazan M, et al. Characterization and assessment of potential microRNAs involved in phosphate-induced aortic calcification. J Cell Physiol 2018; 233:4056–4067..

    2. The article discusses the role of miRNAs as a novel link between phosphate and vascular calcification.

    1. Goettsch C, Hutcheson JD, Aikawa E. MicroRNA in cardiovascular calcification: focus on targets and extracellular vesicle delivery mechanisms. Circ Res 2013; 112:1073–1084..
    1. Filippakopoulos P, Picaud S, Mangos M, et al. Histone recognition and large-scale structural analysis of the human bromodomain family. Cell 2012; 149:214–231..
    1. McLure KG, Gesner EM, Tsujikawa L, et al. RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist. PLoS One 2013; 8:e83190.
    1. Nicholls SJ, Ray KK, Johansson JO, et al. Selective BET protein inhibition with apabetalone and cardiovascular events: a pooled analysis of trials in patients with coronary artery disease. Am J Cardiovasc Drugs 2018; 18:109–115..

    2. The report is the first clinical indication that the BET inhibitor apabetalone can reduce cardiovascular events in CVD patients on top of standard of care.

    1. Haarhaus M, Ray KK, Nicholls SJ, et al. Apabetalone lowers serum alkaline phosphatase and improves cardiovascular risk in patients with cardiovascular disease. Atherosclerosis 2019; 290:59–65..

    2. This is the first clinical report of an association of pharmacologic lowering of serum ALP activity with improved cardiovascular outcome.

    1. Gilham D, Wasiak S, Tsujikawa LM, et al. RVX-208, a BET-inhibitor for treating atherosclerotic cardiovascular disease, raises ApoA-I/HDL and represses pathways that contribute to cardiovascular disease. Atherosclerosis 2016; 247:48–57..
    1. Tsujikawa LM, Fu L, Das S, et al. Apabetalone (RVX-208) reduces vascular inflammation in vitro and in CVD patients by a BET-dependent epigenetic mechanism. Clin Epigenetics 2019; 11:102.
    1. Wasiak S, Gilham D, Daze E, et al. Downregulation of the complement cascade in vitro, in mice and in patients with cardiovascular disease by the BET protein inhibitor apabetalone (RVX-208). J Cardiovasc Transl Res 2017; 10:337–347..
    1. Kulikowski E, Halliday C, Johansson J, et al. Apabetalone mediated epigenetic modulation is associated with favorable kidney function and alkaline phosphatase profile in patients with chronic kidney disease. Kidney Blood Press Res 2018; 43:449–457..
    1. Gilham D, Tsujikawa LM, Sarsons CD, et al. Apabetalone downregulates factors and pathways associated with vascular calcification. Atherosclerosis 2019; 280:75–84..

    2. The article is the first demonstration that BET proteins are involved in epigenetic changes leading to calcification of vascular smooth muscle cells, a process ameliorated with BET inhibitors.

    1. Baud’huin M, Lamoureux F, Jacques C, et al. Inhibition of BET proteins and epigenetic signaling as a potential treatment for osteoporosis. Bone 2017; 94:10–21..
    1. Lamoureux F, Baud’huin M, Rodriguez Calleja L, et al. Selective inhibition of BET bromodomain epigenetic signalling interferes with the bone-associated tumour vicious cycle. Nat Commun 2014; 5:3511.
    1. Meng S, Zhang L, Tang Y, et al. BET inhibitor JQ1 blocks inflammation and bone destruction. J Dent Res 2014; 93:657–662..
    1. Park-Min KH, Lim E, Lee MJ, et al. Inhibition of osteoclastogenesis and inflammatory bone resorption by targeting BET proteins and epigenetic regulation. Nat Commun 2014; 5:5418.
    1. Gjoksi B, Ghayor C, Siegenthaler B, et al. The epigenetically active small chemical N-methyl pyrrolidone (NMP) prevents estrogen depletion induced osteoporosis. Bone 2015; 78:114–121..
    1. Brown JD, Lin CY, Duan Q, et al. NF-kappaB directs dynamic super enhancer formation in inflammation and atherogenesis. Mol Cell 2014; 56:219–231..
    1. Jahagirdar R, Attwell S, Marusic S, et al. RVX-297, a BET bromodomain inhibitor, has therapeutic effects in preclinical models of acute inflammation and autoimmune disease. Mol Pharmacol 2017; 92:694–706..
    1. Nicodeme E, Jeffrey KL, Schaefer U, et al. Suppression of inflammation by a synthetic histone mimic. Nature 2010; 468:1119–1123..
    1. Chen TH, Weber FE, Malina-Altzinger J, Ghayor C. Epigenetic drugs as new therapy for tumor necrosis factor-alpha-compromised bone healing. Bone 2019; 127:49–58..
    1. Miguel BS, Ghayor C, Ehrbar M, et al. N-Methyl pyrrolidone as a potent bone morphogenetic protein enhancer for bone tissue regeneration. Tissue Eng Part A 2009; 15:2955–2963..
    1. Ghayor C, Gjoksi B, Dong J, et al. N,N Dimethylacetamide a drug excipient that acts as bromodomain ligand for osteoporosis treatment. Sci Rep 2017; 7:42108.
    1. Li Q, Liu R, Zhao J, Lu Q. N-methyl pyrrolidone (NMP) ameliorates the hypoxia-reduced osteoblast differentiation via inhibiting the NF-kappaB signaling. J Toxicol Sci 2016; 41:701–709..

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