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Wnt Pathway | Preclinical Research

Preclinical Research

 

In osteoarthritis (OA), the Wnt signaling pathway helps drive the fate of mesenchymal stem cells, which is important for the development of bone and cartilage, as well as the maintenance of homeostasis in the joints. Stem cells differentiate into chondrocytes that can form articular cartilage, or osteoblasts that can form bone.1,2

Activated canonical Wnt signaling promotes articular cartilage destruction and excessive bone formation in OA. By inhibiting this process, it may be possible to protect cartilage from catabolic breakdown. In addition, it’s possible that Wnt signaling pathway inhibition to homeostatic levels can regenerate articular cartilage through the formation of articular chondrocytes from tissue-resident stem cells.1,3-8

Increased Wnt signaling elevates β-catenin in intervertebral discs (IVDs) and may contribute to the pathophysiology of degenerative disc disease.14

  • Mechanical stress and inflammation increase Wnt pathway activity in IVDs15,16
  • Wnt signaling triggers the production of enzymes that degrade collagens in the intervertebral matrix, inducing senescence and apoptosis of nucleus pulposus cells—one of the primary cells that compose IVDs17-19
  • Progenitor cells within the nucleus pulposus area of IVDs have the potential to replace dying cells and stimulate disc tissue renewal20,21

In androgenetic alopecia, canonical Wnt signaling that normally induces hair follicles to undergo growth cycles (anagen) by promoting stem cell proliferation and differentiation is restricted. Reactivating this pathway may restore normal hair follicle stem cell differentiation and hair cycle.9

The expression of Wnt-related proteins is decreased during the development of inflammatory bowel disease (IBD).22,23

  • FZD receptors are minimally expressed in colonic mucosa sampled from patients with IBD22
  • Wnt signaling genes are progressively methylated, and therefore inactivated, during the development of IBD-related neoplasia23

Canonical Wnt signaling is also suppressed in ileal Crohn’s disease.24

  • Wnt ligand expression is necessary for the production of antimicrobial peptides in Paneth cells within the small intestine
  • Decreased Wnt signaling reduces transcription of target genes, which may limit the secretion of these peptides and lead to bacterial infiltration and chronic inflammation

Wnt signaling may contribute to abnormal differentiation of tendon-derived stem cells (TDSC) and ectopic ossification, resulting in the pathogenesis of tendinopathy.10

  • An increase in multiple key Wnt pathway mediators, including Wnt-3a, β-catenin, LRP5, and TCF, has been seen in some clinical samples of tendinopathy
  • Increased expression of Wnt-3a induces osteogenic differentiation of TDSCs into cells other than tenocytes, such as osteoblasts. This may reduce the number of TDSCs available for tendon repair, contributing to failed tendon healing and potentially leading to tendinopathy

Decreased canonical Wnt signaling may contribute to decreased bone formation and increased bone marrow adiposity in osteoporosis.25

  • Wnt signaling promotes the formation of bone-producing osteoblasts and decreases osteoclast differentiation
  • β-catenin is a coactivator of FoxOs—transcription factors that protect against oxidative stress
  • As oxidative stress increases with old age, β-catenin is diverted to FoxO-mediated transcription, limiting the formation of osteoblasts and decreasing bone mass
  • By inhibiting genes that inhibit Wnt signaling, it may be possible to increase bone formation

Sclerostin, a protein encoded by the SOST gene, inhibits Wnt signaling by inhibiting LRP5 function.26

  • Increased sclerostin results in fragile bones with lower bone mineral content, while loss of function of the SOST gene can result in higher bone mass26,27
  • Mutations to the SOST gene can regulate bone matrix formation27

The Wnt signaling pathway is implicated in a wide range of cancers.11

  • Wnt signaling stimulates cell proliferation, inhibits cellular senescence, drives the initiation of tumorigenesis, and activates cancer stem cells11
  • In addition to the canonical pathway, β-catenin–independent Wnt signaling also contributes to the metastatic progression of cancer. For example, in cancers such as melanoma, Wnt5A and Wnt11 may promote cell motility and invasiveness through the non-canonical Wnt pathway11,12
  • In pancreatic cancer, Wnt-related genes such as MYC, PPP2R3A, WNT9A, MAP2, TSC2, GATA6, and TCF4 have been shown to be altered. Gene mutations in other cancers include those to the APC, CTNNB1, AXIN1, WTX, and TCF7L2 genes11,13

Wnt signaling is critically important in the initiation and progression of cancers, specifically in colorectal cancers.11

  • Mutations in APC—a negative regulator of β-catenin—have been observed in patients with familial adenomatous polyposis
  • This demonstrates that, as a result of aberrantly activated Wnt signaling, an increase in β-catenin can contribute significantly to tumorigenesis in the colon

In addition to the areas mentioned, promising Wnt research provides the framework for further areas of discovery, including

  • Type 2 diabetes mellitus28
  • Obesity29
  • Psoriasis30
  • Rheumatoid arthritis31
  • Age-related macular degeneration32
  • Hearing (ear hair cells)33
  • Neural regeneration34
  • Liver fibrosis35
  • Nonalcoholic steatohepatitis36
  • Wound healing37
  • Oncology
    • Pancreatic cancer34
    • Colorectal cancer39
    • Hepatocellular carcinoma38
    • Gastric cancer41
    • Lung cancer42
    • Triple-negative breast cancer43
    • Ovarian cancer44
    • Endometrial cancer45
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References: 1. Chun JS, Oh H, Yang S, Park M. Wnt signaling in cartilage development and degeneration. BMB Rep. 2008;41(7):485-494. 2. Zhou Y, Wang T, Hamilton JL, Chen D. Wnt/β-catenin signaling in osteoarthritis and in other forms of arthritis. Curr Rheumatol Rep. 2017;19(9):53. doi:10.1007/s11926-017-0679-z. 3. Zhu M, Tang D, Wu Q, et al. Activation of beta-catenin signaling in articular chondrocytes leads to osteoarthritis-like phenotype in adult beta-catenin conditional activation mice. J Bone Miner Res. 2009;24(1):12-21. 4. Deshmukh V, Hu H, Barroga C, et al. A small-molecule inhibitor of the Wnt pathway (SM04690) as a potential disease modifying agent for the treatment of osteoarthritis of the knee. Osteoarthritis Cartilage. 2018;26(1):18-27. 5. Rudnicki JA, Brown AM. Inhibition of chondrogenesis by Wnt gene expression in vivo and in vitro. Dev Biol. 1997;185(1):104-118. 6. Nalesso G, Thomas BL, Sherwood JC, et al. WNT16 antagonises excessive canonical WNT activation and protects cartilage in osteoarthritis. Ann Rheum Dis. 2017;76(1):218-226. 7. Lories RJ, Corr M, Lane NE. To Wnt or not to Wnt: the bone and joint health dilemma. Nat Rev Rheumatol. 2013;9(6):328-339. 8. Monteagudo S, Cornelis FMF, Aznar-Lopez C, et al. DOT1L safeguards cartilage homeostasis and protects against osteoarthritis. Nat Commun. 2017;8:15889. doi:10.1038/ncomms15889. 9. Leirós GJ, Attorresi AI, Balañá ME. Hair follicle stem cell differentiation is inhibited through cross-talk between Wnt/β-catenin and androgen signalling in dermal papilla cells from patients with androgenetic alopecia. Br J Dermatol. 2012;166(5):1035-1042. 10. Lui PP, Lee YW, Wong YM, Zhang X, Dai K, Rolf CG. Expression of Wnt pathway mediators in metaplasic tissue in animal model and clinical samples of tendinopathy. Rheumatology (Oxford). 2013;52(9):1609-1618. 11. Anastas JN, Moon RT. WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer. 2013;13(1):11-26. 12. Moon RT, Kohn AD, De Ferrari GV, Kaykas A. WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet. 2004;5(9):691-701. 13. Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321(5897):1801-1806. 14. Hiyama A, Sakai D, Tanaka M, et al. The relationship between the Wnt/β-catenin and TGF-β/BMP signals in the intervertebral disc cell. J Cell Physiol. 2011;226(5):1139-1148. 15. Xu HG, Zheng Q, Song JX, et al. Intermittent cyclic mechanical tension promotes endplate cartilage degeneration via canonical Wnt signaling pathway and E-cadherin/β-catenin complex cross-talk. Osteoarthritis Cartilage. 2016;24(1):158-168. 16. Hiyama A, Yokoyama K, Nukaga T, Sakai D, Mochida J. A complex interaction between Wnt signaling and TNF-α in nucleus pulposus cells. Arthritis Res Ther. 2013;15(6):R189. doi:10.1186/ar4379. 17. Wang M, Tang D, Shu B, et al. Conditional activation of β-catenin signaling in mice leads to severe defects in intervertebral disc tissue. Arthritis Rheum. 2012;64(8):2611-2623. 18. Hiyama A, Sakai D, Risbud MV, et al. Enhancement of intervertebral disc cell senescence by WNT/β-catenin signaling-induced matrix metalloproteinase expression. Arthritis Rheum. 2010;62(10):3036-3047. 19. Sang C, Cao X, Chen F, Yang X, Zhang Y. Differential characterization of two kinds of stem cells isolated from rabbit nucleus pulposus and annulus fibrosus. Stem Cells Int. 2016;2016:8283257. doi:10.1155/2016/8283257. 20. Risbud MV, Shapiro IM. Notochordal cells in the adult intervertebral disc: new perspective on an old question. Crit Rev Eukaryot Gene Expr. 2011;21(1):29-41. 21. Sakai D, Nakamura Y, Nakai T, et al. Exhaustion of nucleus pulposus progenitor cells with ageing and degeneration of the intervertebral disc. Nat Commun. 2012;3:1264. doi:10.1038/ncomms2226. 22. You XJ, Bryant PJ, Jurnak F, Holcombe RF. Expression of Wnt pathway components frizzled and disheveled in colon cancer arising in patients with inflammatory bowel disease. Oncol Rep. 2007;18(3):691-694. 23. Dhir M, Montgomery EA, Glöckner SC, et al. Epigenetic regulation of WNT signaling pathway genes in inflammatory bowel disease (IBD) associated neoplasia. J Gastrointest Surg. 2008;12(10):1745-1753. 24. Armbruster NS, Stange EF, Wehkamp J. In the Wnt of paneth cells: immune-epithelial crosstalk in small intestinal Crohn's disease. Front Immunol. 2017;8:1204. doi:10.3389/fimmu.2017.01204. 25. Manolagas SC. Wnt signaling and osteoporosis. Maturitas. 2014;78(3):233-237. 26. Kahn M. Can we safely target the WNT pathway? Nat Rev Drug Discov. 2014;13(7):513-532. 27. Winkler DG, Sutherland MK, Geoghegan JC, et al. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J. 2003;22(23):6267-6276. 28. Lee SH, Demeterco C, Geron I, Abrahamsson A, Levine F, Itkin-Ansari P. Islet specific Wnt activation in human type II diabetes. Exp Diabetes Res. 2008;2008:728763. doi:10.1155/2008/728763. 29. Fuster JJ, Zuriaga MA, Ngo DT, et al. Noncanonical Wnt signaling promotes obesity-induced adipose tissue inflammation and metabolic dysfunction independent of adipose tissue expansion. Diabetes. 2015;64(4):1235-1248. 30. Gudjonsson JE, Johnston A, Stoll SW, et al. Evidence for altered Wnt signaling in psoriatic skin. J Invest Dermatol. 2010;130(7):1849-1859. 31. Sen M. Wnt signalling in rheumatoid arthritis. Rheumatology (Oxford). 2005;44(6):708-713. 32. Tuo J, Wang Y, Cheng R, et al. Wnt signaling in age-related macular degeneration: human macular tissue and mouse model. J Transl Med. 2015;13:330. doi:10.1186/s12967-015-0683-x. 33. Shi F, Hu L, Jacques BE, Mulvaney JF, Dabdoub A, Edge AS. β-catenin is required for hair-cell differentiation in the cochlea. J Neurosci. 2014;34(19):6470-6479. 34. Liu Y, Wang X, Lu CC, et al. Repulsive Wnt signaling inhibits axon regeneration after CNS injury. J Neurosci. 2008;28(33):8376-8382. 35. Akhmetshina A, Palumbo K, Dees C, et al. Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis. Nat Commun. 2012;3:735. doi:10.1038/ncomms1734. 36. Wang S, Song K, Srivastava R, et al. Nonalcoholic fatty liver disease induced by noncanonical Wnt and its rescue by Wnt3a. FASEB J. 2015;29(8):3436-3445. 37. Whyte JL, Smith AA, Liu B, et al. Augmenting endogenous Wnt signaling improves skin wound healing. PLoS ONE. 2013;8(10):e76883. doi:10.1371/journal.pone.0076883. 38. Zhang Y, Morris JP 4th, Yan W, et al. Canonical wnt signaling is required for pancreatic carcinogenesis. Cancer Res. 2013;73(15):4909-4922. 39. Schatoff EM, Leach BI, Dow LE. Wnt signaling and colorectal cancer. Curr Colorectal Cancer Rep. 2017;13(2):101-110. doi:10.1007/s11888-017-0354-9. 40. Vilchez V, Turcios L, Marti F, Gedaly R. Targeting Wnt/β-catenin pathway in hepatocellular carcinoma treatment. World J Gastroenterol. 2016;22(2):823-32. doi:10.3748/wjg.v22.i2.823. 41. Chiurillo MA. Role of the Wnt/β-catenin pathway in gastric cancer: an in-depth literature review. World J Exp Med. 2015;5(2):84-102. 42. Rapp J, Jaromi L, Kvell K, Miskei G, Pongracz JE. WNT signaling - lung cancer is no exception. Respir Res. 2017;18(1):167. doi:10.1186/s12931-017-0650-6. 43. Pohl SG, Brook N, Agostino M, Arfuso F, Kumar AP, Dharmarajan A. Wnt signaling in triple-negative breast cancer. Oncogenesis. 2017;6(4):e310. doi:10.1038/oncsis.2017.14. 44. Arend RC, Londoño-joshi AI, Straughn JM, Buchsbaum DJ. The Wnt/β-catenin pathway in ovarian cancer: a review. Gynecol Oncol. 2013;131(3):772-779. 45. Markowska A, Pawałowska M, Lubin J, Markowska J. Signalling pathways in endometrial cancer. Contemp Oncol (Pozn). 2014;18(3):143-148.
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