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