Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYJM80N)

• DOT Name: Asporin (ASPN)
• Synonyms: Periodontal ligament-associated protein 1; PLAP-1
• Gene Name: ASPN
• Related Disease:
  Arthropathy
  Exanthem
  Gastric cancer
  Intervertebral disc degeneration
  Keloid
  Lhermitte-Duclos disease
  Metastatic prostate carcinoma
  Neoplasm
  Stomach cancer
  Pancreatic cancer
  Advanced cancer
  Colorectal carcinoma
  Knee osteoarthritis
  Periodontitis
  Type-1 diabetes
• UniProt ID: ASPN_HUMAN
• Pfam ID: PF13855 ; PF01462
• Sequence:
  MKEYVLLLFLALCSAKPFFSPSHIALKNMMLKDMEDTDDDDDDDDDDDDDDEDNSLFPTR
  EPRSHFFPFDLFPMCPFGCQCYSRVVHCSDLGLTSVPTNIPFDTRMLDLQNNKIKEIKEN
  DFKGLTSLYGLILNNNKLTKIHPKAFLTTKKLRRLYLSHNQLSEIPLNLPKSLAELRIHE
  NKVKKIQKDTFKGMNALHVLEMSANPLDNNGIEPGAFEGVTVFHIRIAEAKLTSVPKGLP
  PTLLELHLDYNKISTVELEDFKRYKELQRLGLGNNKITDIENGSLANIPRVREIHLENNK
  LKKIPSGLPELKYLQIIFLHSNSIARVGVNDFCPTVPKMKKSLYSAISLFNNPVKYWEMQ
  PATFRCVLSRMSVQLGNFGM
• Function: Negatively regulates periodontal ligament (PDL) differentiation and mineralization to ensure that the PDL is not ossified and to maintain homeostasis of the tooth-supporting system. Inhibits BMP2-induced cytodifferentiation of PDL cells by preventing its binding to BMPR1B/BMP type-1B receptor, resulting in inhibition of BMP-dependent activation of SMAD proteins. Critical regulator of TGF-beta in articular cartilage and plays an essential role in cartilage homeostasis and osteoarthritis (OA) pathogenesis. Negatively regulates chondrogenesis in the articular cartilage by blocking the TGF-beta/receptor interaction on the cell surface and inhibiting the canonical TGF-beta/Smad signal. Binds calcium and plays a role in osteoblast-driven collagen biomineralization activity.
• Tissue Specificity: Higher levels in osteoarthritic articular cartilage, aorta, uterus. Moderate expression in small intestine, heart, liver, bladder, ovary, stomach, and in the adrenal, thyroid, and mammary glands. Low expression in trachea, bone marrow, and lung. Colocalizes with TGFB1 in chondrocytes within osteoarthritic (OA) lesions of articular cartilage.
• Reactome Pathway: ECM proteoglycans (R-HSA-3000178)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthropathy	DISVEERK	Definitive	Biomarker	[1]
Exanthem	DISAFOQN	Strong	Biomarker	[2]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[3]
Intervertebral disc degeneration	DISG3AIM	Strong	Altered Expression	[4]
Keloid	DISV09JY	Strong	Biomarker	[5]
Lhermitte-Duclos disease	DIS87XW7	Strong	Biomarker	[6]
Metastatic prostate carcinoma	DISVBEZ9	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[3]
Pancreatic cancer	DISJC981	moderate	Biomarker	[9]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[10]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[10]
Knee osteoarthritis	DISLSNBJ	Limited	Biomarker	[11]
Periodontitis	DISI9JOI	Limited	Biomarker	[12]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Asporin (ASPN).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Asporin (ASPN).	[14]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Asporin (ASPN).	[15]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Asporin (ASPN).	[16]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Asporin (ASPN).	[17]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Asporin (ASPN).	[18]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Asporin (ASPN).	[19]

References

• [1] Expression, regulation and function of asporin, a susceptibility gene in common bone and joint diseases.Curr Med Chem. 2008;15(7):724-8. doi: 10.2174/092986708783885237.
• [2] Periodontal ligament-associated protein-1 gets involved in the development of osseous eruption canal.J Mol Histol. 2019 Feb;50(1):35-42. doi: 10.1007/s10735-018-9805-0. Epub 2018 Dec 3.
• [3] Asporin promotes cell proliferation via interacting with PSMD2 in gastric cancer.Front Biosci (Landmark Ed). 2019 Jun 1;24(6):1178-1189. doi: 10.2741/4774.
• [4] IL-1 increases asporin expression via the NF-B p65 pathway in nucleus pulposus cells during intervertebral disc degeneration.Sci Rep. 2017 Jun 23;7(1):4112. doi: 10.1038/s41598-017-04384-3.
• [5] Aberrant connective tissue differentiation towards cartilage and bone underlies human keloids in African Americans.Exp Dermatol. 2017 Aug;26(8):721-727. doi: 10.1111/exd.13271. Epub 2017 Feb 28.
• [6] Association of the asporin D14 allele with lumbar-disc degeneration in Asians.Am J Hum Genet. 2008 Mar;82(3):744-7. doi: 10.1016/j.ajhg.2007.12.017. Epub 2008 Feb 21.
• [7] Germline Variants in Asporin Vary by Race, Modulate the Tumor Microenvironment, and Are Differentially Associated with Metastatic Prostate Cancer.Clin Cancer Res. 2016 Jan 15;22(2):448-58. doi: 10.1158/1078-0432.CCR-15-0256. Epub 2015 Oct 7.
• [8] Multifaceted Roles of Asporin in Cancer: Current Understanding.Front Oncol. 2019 Sep 24;9:948. doi: 10.3389/fonc.2019.00948. eCollection 2019.
• [9] Asporin promotes pancreatic cancer cell invasion and migration by regulating the epithelial-to-mesenchymal transition (EMT) through both autocrine and paracrine mechanisms.Cancer Lett. 2017 Jul 10;398:24-36. doi: 10.1016/j.canlet.2017.04.001. Epub 2017 Apr 9.
• [10] Cytoplasmic Asporin promotes cell migration by regulating TGF-/Smad2/3 pathway and indicates a poor prognosis in colorectal cancer.Cell Death Dis. 2019 Feb 6;10(2):109. doi: 10.1038/s41419-019-1376-9.
• [11] Identifying the role of ASPN and COMP genes in knee osteoarthritis development.J Orthop Surg Res. 2019 Oct 29;14(1):337. doi: 10.1186/s13018-019-1391-7.
• [12] Periodontal ligament-associated protein-1 gets involved in experimental periodontitis.J Periodontal Res. 2019 Apr;54(2):180-189. doi: 10.1111/jre.12618. Epub 2018 Oct 8.
• [13] 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.
• [14] 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.
• [15] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [16] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [17] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [18] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [19] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.