Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXJRUW0)

• DOT Name: Matrix extracellular phosphoglycoprotein (MEPE)
• Synonyms: Osteoblast/osteocyte factor 45; OF45; Osteoregulin
• Gene Name: MEPE
• Related Disease:
  Familial tumoral calcinosis
  Autosomal dominant hypophosphatemic rickets
  Bone disease
  Breast neoplasm
  Cardiovascular disease
  Cervical cancer
  Cervical carcinoma
  Coronary atherosclerosis
  Crohn disease
  Cytomegalovirus infection
  Gout
  Hypophosphatemia
  Liposarcoma
  Malignant hyperthermia of anesthesia
  Matthew-Wood syndrome
  Squamous cell carcinoma
  Stroke
  Ulcerative colitis
  X-linked dominant hypophosphatemic rickets
  Xeroderma pigmentosum
  Epstein barr virus infection
  High blood pressure
  Osteoarthritis
  Arthritis
  Breast cancer
  Breast carcinoma
  Hypophosphatemic rickets
  Neoplasm
  Osteoporosis
  Type-1 diabetes
  Vitamin D-dependent rickets, type 2
• UniProt ID: MEPE_HUMAN
• Pfam ID: PF07175
• Sequence:
  MRVFCVGLLLFSVTWAAPTFQPQTEKTKQSCVEEQRQEEKNKDNIGFHHLGKRINQELSS
  KENIVQERKKDLSLSEASENKGSSKSQNYFTNRQRLNKEYSISNKENTHNGLRMSIYPKS
  TGNKGFEDGDDAISKLHDQEEYGAALIRNNMQHIMGPVTAIKLLGEENKENTPRNVLNII
  PASMNYAKAHSKDKKKPQRDSQAQKSPVKSKSTHRIQHNIDYLKHLSKVKKIPSDFEGSG
  YTDLQERGDNDISPFSGDGQPFKDIPGKGEATGPDLEGKDIQTGFAGPSEAESTHLDTKK
  PGYNEIPEREENGGNTIGTRDETAKEADAVDVSLVEGSNDIMGSTNFKELPGREGNRVDA
  GSQNAHQGKVEFHYPPAPSKEKRKEGSSDAAESTNYNEIPKNGKGSTRKGVDHSNRNQAT
  LNEKQRFPSKGKSQGLPIPSRGLDNEIKNEMDSFNGPSHENIITHGRKYHYVPHRQNNST
  RNKGMPQGKGSWGRQPHSNRRFSSRRRDDSSESSDSGSSSESDGD
• Function: Promotes renal phosphate excretion and inhibits intestinal phosphate absorption. Promotes bone mineralization by osteoblasts and cartilage mineralization by chondrocytes. Regulates the mineralization of the extracellular matrix of the craniofacial complex, such as teeth, bone and cartilage. Promotes dental pulp stem cell proliferation and differentiation.
• Tissue Specificity: Detected in urine (at protein level) . Expressed by osteoblasts . Expressed by stem cells in dental pulp . Expressed by mesenchymal cells in dental papilla and dental pulp . Expressed in teeth, specifically in decidious dentin . Expressed in ondotoblasts . Expressed in salivary glands . Secreted from oncogenic hypophosphatemic tumors .
• KEGG Pathway: ECM-receptor interaction (hsa04512)
• Reactome Pathway:
  Post-translational protein phosphorylation (R-HSA-8957275)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial tumoral calcinosis	DISYJZKG	Definitive	Genetic Variation	[1]
Autosomal dominant hypophosphatemic rickets	DISG799S	Strong	Biomarker	[2]
Bone disease	DISE1F82	Strong	Genetic Variation	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[5]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[6]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[6]
Coronary atherosclerosis	DISKNDYU	Strong	Genetic Variation	[7]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[8]
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[9]
Gout	DISHC0U7	Strong	Genetic Variation	[10]
Hypophosphatemia	DIS9DZYF	Strong	Biomarker	[11]
Liposarcoma	DIS8IZVM	Strong	Biomarker	[12]
Malignant hyperthermia of anesthesia	DISYC9XI	Strong	Genetic Variation	[13]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[14]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[15]
Stroke	DISX6UHX	Strong	Biomarker	[5]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[16]
X-linked dominant hypophosphatemic rickets	DISU3OP6	Strong	Biomarker	[2]
Xeroderma pigmentosum	DISQ9H19	Strong	Biomarker	[17]
Epstein barr virus infection	DISOO0WT	moderate	Biomarker	[18]
High blood pressure	DISY2OHH	moderate	Genetic Variation	[19]
Osteoarthritis	DIS05URM	moderate	Biomarker	[20]
Arthritis	DIST1YEL	Disputed	Biomarker	[21]
Breast cancer	DIS7DPX1	Disputed	Genetic Variation	[22]
Breast carcinoma	DIS2UE88	Disputed	Genetic Variation	[22]
Hypophosphatemic rickets	DIS7XTW5	Limited	Biomarker	[23]
Neoplasm	DISZKGEW	Limited	Altered Expression	[6]
Osteoporosis	DISF2JE0	Limited	Biomarker	[24]
Type-1 diabetes	DIS7HLUB	Limited	Genetic Variation	[25]
Vitamin D-dependent rickets, type 2	DISZHFC3	Limited	Biomarker	[23]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Phosphate	DMUXQG7	Approved	Matrix extracellular phosphoglycoprotein (MEPE) affects the metabolism of Phosphate.	[30]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Matrix extracellular phosphoglycoprotein (MEPE).	[26]

3 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Matrix extracellular phosphoglycoprotein (MEPE).	[27]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Matrix extracellular phosphoglycoprotein (MEPE).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Matrix extracellular phosphoglycoprotein (MEPE).	[29]

References

• [1] The role of mutant UDP-N-acetyl-alpha-D-galactosamine-polypeptide N-acetylgalactosaminyltransferase 3 in regulating serum intact fibroblast growth factor 23 and matrix extracellular phosphoglycoprotein in heritable tumoral calcinosis.J Clin Endocrinol Metab. 2006 Oct;91(10):4037-42. doi: 10.1210/jc.2006-0305. Epub 2006 Jul 25.
• [2] FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization.Am J Physiol Endocrinol Metab. 2003 Jul;285(1):E1-9. doi: 10.1152/ajpendo.00016.2003.
• [3] Variants affecting diverse domains of MEPE are associated with two distinct bone disorders, a craniofacial bone defect and otosclerosis.Genet Med. 2019 May;21(5):1199-1208. doi: 10.1038/s41436-018-0300-5. Epub 2018 Oct 5.
• [4] Hypermethylation of the GSTP1 promoter region in breast cancer is associated with prognostic clinicopathological parameters.Neoplasma. 2010;57(1):35-40. doi: 10.4149/neo_2010_01_035.
• [5] Risk and Age of Cardiovascular Event in Women with Metabolic Syndrome: Menopause Age in Focus.Metab Syndr Relat Disord. 2018 Apr;16(3):127-134. doi: 10.1089/met.2017.0096. Epub 2018 Feb 13.
• [6] Regulatory roles of miRNA-758 and matrix extracellular phosphoglycoprotein in cervical cancer.Exp Ther Med. 2017 Oct;14(4):2789-2794. doi: 10.3892/etm.2017.4887. Epub 2017 Aug 4.
• [7] Association of +45(T/G) and +276(G/T) polymorphisms in the adiponectin gene with coronary artery disease in a population of Iranian patients with type 2 diabetes.Mol Biol Rep. 2012 Apr;39(4):3791-7. doi: 10.1007/s11033-011-1156-9. Epub 2011 Jul 10.
• [8] Eosinophil associated genes in the inflammatory bowel disease 4 region: correlation to inflammatory bowel disease revealed.World J Gastroenterol. 2012 Nov 28;18(44):6409-19; discussion p. 6417-8. doi: 10.3748/wjg.v18.i44.6409.
• [9] Clinical and Economic Impact of Cytomegalovirus Infection among Children Undergoing Allogeneic Hematopoietic Cell Transplantation.Biol Blood Marrow Transplant. 2019 Jun;25(6):1253-1259. doi: 10.1016/j.bbmt.2018.11.028. Epub 2018 Nov 29.
• [10] Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet. 2013 Feb;45(2):145-54. doi: 10.1038/ng.2500. Epub 2012 Dec 23.
• [11] Genetic diseases of renal phosphate handling.Nephrol Dial Transplant. 2014 Sep;29 Suppl 4:iv45-54. doi: 10.1093/ndt/gfu217.
• [12] MDM2 amplification and loss of heterozygosity at Rb and p53 genes: no simultaneous alterations in the oncogenesis of liposarcomas.J Cancer Res Clin Oncol. 1998;124(10):532-40. doi: 10.1007/s004320050211.
• [13] Polymorphisms and deduced amino acid substitutions in the coding sequence of the ryanodine receptor (RYR1) gene in individuals with malignant hyperthermia.Genomics. 1992 Aug;13(4):1247-54. doi: 10.1016/0888-7543(92)90042-q.
• [14] Clinical significance of GNAS mutation in intraductal papillary mucinous neoplasm of the pancreas with concomitant pancreatic ductal adenocarcinoma.Pancreas. 2015 Mar;44(2):311-20. doi: 10.1097/MPA.0000000000000258.
• [15] DNA sequences of human papillomavirus types 11, 16 or 18 in invasive cervical carcinoma of Western Australian women.Immunol Cell Biol. 1987 Feb;65 ( Pt 1):77-84. doi: 10.1038/icb.1987.9.
• [16] Health Care Cost for Children Newly Diagnosed With Inflammatory Bowel Disease.Inflamm Bowel Dis. 2020 Mar 4;26(4):635-640. doi: 10.1093/ibd/izz183.
• [17] Clinical symptoms and DNA repair characteristics of xeroderma pigmentosum patients from Germany.Cancer Res. 1991 Jul 1;51(13):3456-70.
• [18] Role of sexual behavior in the acquisition of asymptomatic Epstein-Barr virus infection: a longitudinal study.Pediatr Infect Dis J. 2005 Jun;24(6):498-502. doi: 10.1097/01.inf.0000164709.40358.b6.
• [19] Prevalence of hypertension and associated risk factors in people with long-term spinal cord injury living in the Netherlands.Disabil Rehabil. 2017 May;39(9):919-927. doi: 10.3109/09638288.2016.1172349. Epub 2016 May 9.
• [20] Emerging Trend in the Pharmacotherapy of Osteoarthritis.Front Endocrinol (Lausanne). 2019 Jul 2;10:431. doi: 10.3389/fendo.2019.00431. eCollection 2019.
• [21] Transport and distribution of (45)Ca(2+) in the perfused rat liver and the influence of adjuvant-induced arthritis.Biochim Biophys Acta. 2013 Jan;1832(1):249-62. doi: 10.1016/j.bbadis.2012.10.008. Epub 2012 Oct 12.
• [22] Drivers of advanced stage at breast cancer diagnosis in the multicountry African breast cancer - disparities in outcomes (ABC-DO) study.Int J Cancer. 2018 Apr 15;142(8):1568-1579. doi: 10.1002/ijc.31187. Epub 2017 Dec 23.
• [23] Clinical and molecular heterogeneity in a large series of patients with hypophosphatemic rickets.Bone. 2015 Oct;79:143-9. doi: 10.1016/j.bone.2015.05.040. Epub 2015 Jun 5.
• [24] Molecular disease map of bone characterizing the postmenopausal osteoporosis phenotype.J Bone Miner Res. 2011 Aug;26(8):1793-801. doi: 10.1002/jbmr.396.
• [25] Very High Prevalence of Frozen Shoulder in Patients With Type 1 Diabetes of ?5 Years' Duration: The Dialong Shoulder Study.Arch Phys Med Rehabil. 2017 Aug;98(8):1551-1559. doi: 10.1016/j.apmr.2017.01.020. Epub 2017 Feb 17.
• [26] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [27] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [28] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [29] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [30] Serum levels of matrix extracellular phosphoglycoprotein (MEPE) in normal humans correlate with serum phosphorus, parathyroid hormone and bone mineral density. J Clin Endocrinol Metab. 2004 Aug;89(8):4158-61. doi: 10.1210/jc.2003-032031.