Prospects and Perspectives for WISP1 (CCN4) in Diabetes Mellitus

Author(s): Kenneth Maiese*

Journal Name: Current Neurovascular Research

Volume 17 , Issue 3 , 2020

Become EABM
Become Reviewer
Call for Editor


The prevalence of diabetes mellitus (DM) continues to increase throughout the world. In the United States (US) alone, approximately ten percent of the population is diagnosed with DM and another thirty-five percent of the population is considered to have prediabetes. Yet, current treatments for DM are limited and can fail to block the progression of multi-organ failure over time. Wnt1 inducible signaling pathway protein 1 (WISP1), also known as CCN4, is a matricellular protein that offers exceptional promise to address underlying disease progression and develop innovative therapies for DM. WISP1 holds an intricate relationship with other primary pathways of metabolism that include protein kinase B (Akt), mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), and mammalian forkhead transcription factors (FoxOs). WISP1 is an exciting prospect to foster vascular as well as neuronal cellular protection and regeneration, control cellular senescence, block oxidative stress injury, and maintain glucose homeostasis. However, under some scenarios WISP1 can promote tumorigenesis, lead to obesity progression with adipocyte hyperplasia, foster fibrotic hepatic disease, and lead to dysregulated inflammation with the progression of DM. Given these considerations, it is imperative to further elucidate the complex relationship WISP1 holds with other vital metabolic pathways to successfully develop WISP1 as a clinically effective target for DM and metabolic disorders.

Keywords: Akt, AMP activated protein kinase (AMPK), autophagy, cancer, CCN4, diabetes mellitus, forkhead transcription factors, FoxO, inflammation, interleukin 18 (IL-18), mechanistic target of rapamycin (mTOR), oxidative stress, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), sirtuin, stem cells, Wnt1 inducible signaling pathway protein 1 (WISP1), WISP-1, wingless, Wnt.

Centers for Disease Control and Prevention. National Diabetes Statistics Report 2020. 2020. CS 314227-A:1-30.
Maiese K. Cognitive impairment with diabetes mellitus and metabolic disease: innovative insights with the mechanistic target of rapamycin and circadian clock gene pathways. Expert Rev Clin Pharmacol 2020; 13(1): 23-34.
[] [PMID: 31794280]
Coca SG, Ismail-Beigi F, Haq N, Krumholz HM, Parikh CR. Role of intensive glucose control in development of renal end points in type 2 diabetes mellitus: systematic review and meta-analysis intensive glucose control in type 2 diabetes. Arch Intern Med 2012; 172(10): 761-9.
[] [PMID: 22636820]
Lee JH, Lee JH, Jin M, et al. Diet control to achieve euglycemia induces significant loss of heart and liver weight via increased autophagy compared with ad libitum diet in diabetic rats. Exp Mol Med 2014.: : 46e111
[] [PMID: 25168310]
Maiese K, Li F, Chong ZZ, Shang YC. The Wnt signaling pathway: aging gracefully as a protectionist? Pharmacol Ther 2008; 118(1): 58-81.
[] [PMID: 18313758]
Maiese K. Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR. Neural Regen Res 2016; 11(3): 372-85.
[] [PMID: 27127460]
Maiese K. Picking a bone with WISP1 (CCN4): New strategies against degenerative joint disease. J Transl Sci 2016; 1(3): 83-5.
[] [PMID: 26893943]
Jia S, Qu T, Feng M, et al. Association of Wnt1-inducible signaling pathway protein-1 with the proliferation, migration and invasion in gastric cancer cells. Tumour Biol 2017; 39(6): : 1010428317699755
[] [PMID: 28618940]
Maiese K. WISP1: Clinical insights for a proliferative and restorative member of the CCN family. Curr Neurovasc Res 2014; 11(4): 378-89.
[] [PMID: 25219658]
Maiese K. New Insights for Oxidative Stress and Diabetes Mellitus Oxid Med Cell Longev 2015; 2015(2015): : 875961
Lim HW, Lee JE, Shin SJ, et al. Identification of differentially expressed mRNA during pancreas regeneration of rat by mRNA differential display. Biochem Biophys Res Commun 2002; 299(5): 806-12.
[] [PMID: 12470650]
Murahovschi V, Pivovarova O, Ilkavets I, et al. WISP1 is a novel adipokine linked to inflammation in obesity. Diabetes 2015; 64(3): 856-66.
[] [PMID: 25281430]
Sahin Ersoy G, Altun Ensari T, Subas S, Giray B, Simsek EE, Cevik O. WISP1 is a novel adipokine linked to metabolic parameters in gestational diabetes mellitus. J Matern Fetal Neonatal Med 2016; 1-5.
[PMID: 27267804]
Wang AR, Yan XQ, Zhang C, et al. Characterization of Wnt1-inducible Signaling Pathway Protein-1 in Obese Children and Adolescents. Current medical science 2018; 38(5): 868-74.
Hill JH, Solt C, Foster MT. Obesity associated disease risk: the role of inherent differences and location of adipose depots. Horm Mol Biol Clin Investig 2018; 33 (2 ): 2018.33.
[] [PMID: 29547393]
Barchetta I, Cimini FA, Capoccia D, et al. WISP1 is a marker of systemic and adipose tissue inflammation in dysmetabolic subjects with or without type 2 Diabetes. J Endocr Soc 2017; 1(6): 660-70.
[] [PMID: 29264519]
Klimontov VV, Bulumbaeva DM, Fazullina ON, et al. Circulating Wnt1-inducible signaling pathway protein-1 (WISP-1/CCN4) is a novel biomarker of adiposity in subjects with type 2 diabetes. J Cell Commun Signal 2020; 14(1): 101-9.
[] [PMID: 31782053]
Guo T, Cao G, Li Y, et al. Signals in Stem Cell Differentiation on Fluorapatite-Modified Scaffolds. J Dent Res 2018; 97(12): 1331-8.
[] [PMID: 29995454]
Maiese K. Novel applications of trophic factors, Wnt and WISP for neuronal repair and regeneration in metabolic disease. Neural Regen Res 2015; 10(4): 518-28.
[] [PMID: 26170801]
Maiese K. Harnessing the Power of SIRT1 and Non-coding RNAs in Vascular Disease. Curr Neurovasc Res 2017; 14(1): 82-8.
[] [PMID: 27897112]
Maiese K, Chong ZZ, Shang YC, Wang S. Targeting disease through novel pathways of apoptosis and autophagy. Expert Opin Ther Targets 2012; 16(12): 1203-14.
[] [PMID: 22924465]
Ye Y, Zhang P, Qian Y, Yin B, Yan M. The Effect of pyrroloquinoline quinone on the expression of WISP1 in traumatic brain injury. Stem Cells Int 2017; 2017: 4782820
[] [PMID: 28883836]
Price RM, Tulsyan N, Dermody JJ, Schwalb M, Soteropoulos P, Castronuovo JJ Jr. Gene expression after crush injury of human saphenous vein: Using microarrays to define the transcriptional profile. J Am Coll Surg 2004; 199(3): 411-8.
[] [PMID: 15325611]
Liu H, Dong W, Lin Z, et al. CCN4 regulates vascular smooth muscle cell migration and proliferation. Mol Cells 2013; 36(2): 112-8.
[] [PMID: 23807044]
Reddy VS, Valente AJ, Delafontaine P, Chandrasekar B. Interleukin-18/WNT1-inducible signaling pathway protein-1 signaling mediates human saphenous vein smooth muscle cell proliferation. J Cell Physiol 2011; 226(12): 3303-15.
[] [PMID: 21321938]
Du J, Klein JD, Hassounah F, Zhang J, Zhang C, Wang XH. Aging increases CCN1 expression leading to muscle senescence. Am J Physiol Cell Physiol 2014; 306(1): C28-36.
[] [PMID: 24196529]
Marchand A, Atassi F, Gaaya A, et al. The Wnt/beta-catenin pathway is activated during advanced arterial aging in humans. Aging Cell 2011; 10(2): 220-32.
[] [PMID: 21108734]
Maiese K. The mechanistic target of rapamycin (mTOR) and the silent mating-type information regulation 2 homolog 1 (SIRT1): oversight for neurodegenerative disorders. Biochem Soc Trans 2018; 46(2): 351-60.
[] [PMID: 29523769]
Shang YC, Chong ZZ, Wang S, Maiese K. Wnt1 inducible signaling pathway protein 1 (WISP1) targets PRAS40 to govern β-amyloid apoptotic injury of microglia. Curr Neurovasc Res 2012; 9(4): 239-49.
[] [PMID: 22873724]
Shang YC, Chong ZZ, Wang S, Maiese K. Tuberous sclerosis protein 2 (TSC2) modulates CCN4 cytoprotection during apoptotic amyloid toxicity in microglia. Curr Neurovasc Res 2013; 10(1): 29-38.
[] [PMID: 23244622]
Chong ZZ, Shang YC, Zhang L, Wang S, Maiese K. Mammalian target of rapamycin: hitting the bull’s-eye for neurological disorders. Oxid Med Cell Longev 2010; 3(6): 374-91.
[] [PMID: 21307646]
Kopp C, Hosseini A, Singh SP, et al. Nicotinic acid increases adiponectin secretion from differentiated bovine preadipocytes through G-protein coupled receptor signaling. Int J Mol Sci 2014; 15(11): 21401-18.
[] [PMID: 25411802]
Maiese K, Chong ZZ, Shang YC, Wang S. mTOR: on target for novel therapeutic strategies in the nervous system. Trends Mol Med 2013; 19(1): 51-60.
[] [PMID: 23265840]
Martínez de Morentin PB, Martinez-Sanchez N, Roa J, et al. Hypothalamic mTOR: the rookie energy sensor. Curr Mol Med 2014; 14(1): 3-21.
[] [PMID: 24236459]
Dong Y, Chen H, Gao J, Liu Y, Li J, Wang J. Molecular machinery and interplay of apoptosis and autophagy in coronary heart disease. J Mol Cell Cardiol 2019; 136: 27-41.
[] [PMID: 31505198]
Pal PB, Sonowal H, Shukla K, Srivastava SK, Ramana KV. Aldose reductase regulates hyperglycemia-induced HUVEC death via SIRT1/AMPK-α1/mTOR pathway. J Mol Endocrinol 2019; 63(1): 11-25.
[] [PMID: 30986766]
Zhang H, Yang X, Pang X, Zhao Z, Yu H, Zhou H. Genistein protects against ox-LDL-induced senescence through enhancing SIRT1/LKB1/AMPK-mediated autophagy flux in HUVECs. Mol Cell Biochem 2019; 455(1-2): 127-34.
[] [PMID: 30443855]
Zhao D, Sun X, Lv S, et al. Salidroside attenuates oxidized low density lipoprotein induced endothelial cell injury via promotion of the AMPK/SIRT1 pathway. Int J Mol Med 2019; 43(6): 2279-90.
[] [PMID: 30942428]
Maiese K. Impacting dementia and cognitive loss with innovative strategies: mechanistic target of rapamycin, clock genes, circular non-coding ribonucleic acids, and Rho/Rock. Neural Regen Res 2019; 14(5): 773-4.
[] [PMID: 30688262]
Wang S, Chong ZZ, Shang YC, Maiese K. Wnt1 inducible signaling pathway protein 1 (WISP1) blocks neurodegeneration through phosphoinositide 3 kinase/Akt1 and apoptotic mitochondrial signaling involving Bad, Bax, Bim, and Bcl-xL. Curr Neurovasc Res 2012; 9(1): 20-31.
[] [PMID: 22272766]
Wang S, Chong ZZ, Shang YC, Maiese K. WISP1 (CCN4) autoregulates its expression and nuclear trafficking of β-catenin during oxidant stress with limited effects upon neuronal autophagy. Curr Neurovasc Res 2012; 9(2): 91-101.
[] [PMID: 22475393]
Wang S, Chong ZZ, Shang YC, Maiese K. WISP1 neuroprotection requires FoxO3a post-translational modulation with autoregulatory control of SIRT1. Curr Neurovasc Res 2013; 10(1): 54-69.
[] [PMID: 23151077]
Jenwitheesuk A, Park S, Wongchitrat P, Tocharus J, Mukda S, Shimokawa I, et al. Comparing the effects of melatonin with caloric restriction in the hippocampus of aging mice: Involvement of Sirtuin1 and the FOXOs pathway. Neurochem Res 2017.
[PMID: 28770437]
Maiese K, Fox O, Fox O. Transcription Factors and Regenerative Pathways in Diabetes Mellitus. Curr Neurovasc Res 2015; 12(4): 404-13.
[] [PMID: 26256004]
Wright LH, Herr DJ, Brown SS, Kasiganesan H, Menick DR. Angiokine Wisp-1 is increased in myocardial infarction and regulates cardiac endothelial signaling. JCI Insight 2018; 3(4): 95824.
[] [PMID: 29467324]
Lukjanenko L, Karaz S, Stuelsatz P, et al. Aging Disrupts Muscle Stem Cell Function by Impairing Matricellular WISP1 Secretion from Fibro-Adipogenic Progenitors. Cell Stem Cell 2019; 24(3): 433-446.e7.
[] [PMID: 30686765]
Marchetti B. Wnt/β-Catenin signaling pathway governs a full program for dopaminergic neuron survival, neurorescue and regeneration in the MPTP mouse model of Parkinson’s Disease. Int J Mol Sci 2018; 19(12): : E3743
[] [PMID: 30477246]
Feng M, Jia S. Dual effect of WISP-1 in diverse pathological processes. Chinese journal of cancer research = Chung-kuo yen cheng yen chiu 2016; 28(6): 553-60.
Tsai HC, Tzeng HE, Huang CY, et al. WISP-1 positively regulates angiogenesis by controlling VEGF-A expression in human osteosarcoma. Cell Death Dis 2017; 8(4): : e2750
[] [PMID: 28406476]
Wang Y, Yang SH, Hsu PW, et al. Impact of WNT1-inducible signaling pathway protein-1 (WISP-1) genetic polymorphisms and clinical aspects of breast cancer. Medicine (Baltimore) 2019; 98(44): : e17854
[] [PMID: 31689877]
Cernea M, Tang W, Guan H, Yang K. Wisp1 mediates Bmp3-stimulated mesenchymal stem cell proliferation. J Mol Endocrinol 2016; 56(1): 39-46.
[] [PMID: 26489765]
Gatica-Andrades M, Vagenas D, Kling J, et al. WNT ligands contribute to the immune response during septic shock and amplify endotoxemia-driven inflammation in mice. Blood Adv 2017; 1(16): 1274-86.
[] [PMID: 29296769]
Gaudreau PO, Clairefond S, Class CA, et al. WISP1 is associated to advanced disease, EMT and an inflamed tumor microenvironment in multiple solid tumors. OncoImmunology 2019; 8(5): : e1581545
[] [PMID: 31069142]
Lu S, Liu H, Lu L, et al. WISP1 overexpression promotes proliferation and migration of human vascular smooth muscle cells via AKT signaling pathway. Eur J Pharmacol 2016; 788: 90-7.
[] [PMID: 27321870]
Mercer KE, Hennings L, Sharma N, et al. Alcohol consumption promotes diethylnitrosamine-induced hepatocarcinogenesis in male mice through activation of the Wnt/β-catenin signaling pathway. Cancer Prev Res (Phila) 2014; 7(7): 675-85.
[] [PMID: 24778325]
Jian YC, Wang JJ, Dong S, et al. Wnt-induced secreted protein 1/CCN4 in liver fibrosis both in vitro and in vivo. Clin Lab 2014; 60(1): 29-35.
[] [PMID: 24600972]
Maiese K, Chong ZZ, Shang YC, Wang S. Novel directions for diabetes mellitus drug discovery. Expert Opin Drug Discov 2013; 8(1): 35-48.
[] [PMID: 23092114]
Chen YZ, Sun DQ, Zheng Y, et al. WISP1 silencing confers protection against epithelial-mesenchymal transition of renal tubular epithelial cells in rats via inactivation of the wnt/β-catenin signaling pathway in uremia. J Cell Physiol 2019; 234(6): 9673-86.
[] [PMID: 30556898]

open access plus

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 28 September, 2020
Page: [327 - 331]
Pages: 5
DOI: 10.2174/1567202617666200327125257

Article Metrics

PDF: 27