Roles of Wnt/β-Catenin Signaling in Osteoporosis, Disease Pathogenesis, and Natural Compound Intervention

Abstract

Osteoblasts primarily originate from mesenchymal stem cells (MSCs) within the bone marrow. These stem cells possess the ability to differentiate into osteoblasts, which are responsible for secreting bone matrix, promoting bone formation, and contributing to bone remodeling. Dysfunction in osteoblast activity can lead to various bone-related disorders, such as osteoporosis, delayed fracture healing, and skeletal deformities. In recent years, due to the adverse effects associated with the use of parathyroid hormone (PTH) analogs, bisphosphonates, and calmodulin-targeting drugs, there has been growing interest in exploring the mechanisms underlying osteoblast differentiation. Researchers are increasingly focusing on identifying natural compounds as potential treatments for osteoporosis. Among the signaling pathways involved, the Wnt/β-catenin pathway is recognized as a key regulator of osteoblast differentiation and a crucial therapeutic target in osteoporosis. However, both upregulation and downregulation of this pathway have been implicated in various diseases, including cancers. This review highlights the role of the Wnt/β-catenin signaling pathway in osteoblast differentiation, examines the association between pathway-related proteins and human diseases, and summarizes recent advancements in the development of natural compounds targeting this pathway for osteoporosis therapy.

INTRODUCTION

The Wnt/β-catenin pathway is a very well-conserved molecular cascade and it controls embryonic development, organogenesis, and tissue maintenance. This pathway is essential in the skeletal system, and is responsible in ensuring the balance between bone deposits and subtraction (Compston et al., 2019; Delany et al., 2000; Zhang et al., 2025). Activation of canonical Wnt signaling leads to stabilization of β-catenin, which is then localized to the nucleus where it induces osteoblast-specific gene expression, which is crucial in matrix synthesis and mineralization. In contrast, the suppression of the pathway impedes osteoblast growth and enhances osteoclast effects, causing skeletal fragility.

Dysregulation of the Wnt/β-catenin pathway has been shown to cause various pathological conditions including osteoporosis and cancer (Lamprecht et al., 2025; Ponzetti and Rucci, 2021). In osteoporosis, inadequacy of Wnt activity inhibits osteoblastogenesis and promotes bone resorption that leads to the reduction in bone mass and worsening of microarchitecture. This is often characterised by high concentrations of Wnt inhibitors like sclerostin and Dickkopf-1 (DKK-1), and inactivating mutations in LRP5. The clinical implication is that there is a higher risk of bone fractures, impaired mobility and a lower quality of life (Martínez-Reina et al., 2021). On the other hand, excessive activation of Wnt/β-catenin signaling has been established as a causal factor in oncogenesis. Mutations in APC, Axin, or β-catenin itself induce pathway activation in the absence of regulation and uncontrolled cell proliferation especially in colorectal, hepatocellular, and breast cancers (Romanowicz and Łukaszewicz-Zając, 2025; Yao et al., 2017).

Dysregulated Wnt signaling also promotes self-renewal of cancer stem cells and metastasis, and increases resistance to chemotherapy, further exacerbating the management of the disease. This paradox reveals a key therapeutic conundrum: although activating Wnt signaling can have a positive effect in osteoporotic patients by stimulating bone formation, it also threatens to drive or accelerate malignant disease. In contrast, the therapeutic use of Wnt/β-catenin inhibitors in cancers may be counterproductive due to negative effects on bone strength and repair (Vlashi et al., 2023). The current approaches to pharmacological intervention in the pathway, such as with sclerostin-neutralizing antibodies, like romosozumab, in osteoporosis or porcupine (PORCN) inhibitors or β-catenin-TCF antagonists in cancer, have demonstrated clinical potential but also highlight the danger of unselectively modulating a pathway.

In recent years, plant-based natural compounds, dietary, and traditional medicines have been identified as possible modulators of the Wnt/β-catenin signaling pathway. Compared to synthetic agents, natural products may target more components of the pathway and at lower potency (Tonk et al., 2022). Phytochemicals, including flavonoids, alkaloids, terpenoids, and polyphenols, are reported to mediate both inhibition and activation of Wnt signaling, which may provide a distinct method toward maintaining homeostasis in the signaling. They have pleiotropic properties, are comparatively safe, and are readily available, making them interesting options in intervening in the disease associated with Wnt deregulation.

The aim of the current review is to summarize and critically discuss the duality of Wnt/β-catenin signaling in skeletal and oncological diseases, especially in osteoporosis and tumor. Furthermore, it examines natural compounds as the precision modulator of the ability to fine-tune pathway activity to produce therapeutic benefits with minimal risks. By correlating the molecular understanding to the clinical point of view, this effort offers a scope through which safer, specific methods can be designed to deal with the high complexity that characterizes Wnt-signaling modulation.

β-CATENIN

β-catenin was initially discovered as a component of adherens junctions, playing a key role in cell–cell adhesion. It was only later that its critical involvement in the Wnt/β-catenin signaling pathway was recognized. Belonging to the Armadillo protein family, β-catenin is encoded by the CTNNB1 gene and features a structurally stable N-terminal region rich in serine and threonine residues (Nichols et al., 2012). An area referred to as the domain of the C-terminal within β-catenin contains 100 amino acids, which activates transcription through binding to histone acetyltransferases and chromatin remodeling factors along with transcriptional cofactors. A core portion within β-catenin extends from R1 to R12 in twelve Armadillo repeats, creating a stabilizing rod-shaped superhelical structure that blocks protein degradation (Graham et al., 2000). The stable arrangement of β-catenin within the cytoplasm controls the signaling of Wnt/β-catenin because it allows its critical role as a transcriptional element to send signals to the nucleus (Cheng et al., 2020). The vital process of disease development relies on β-catenin, which performs its essential function as a fundamental molecule in this signaling pathway. According to scientific studies, FAT4 protein binding inhibits β-catenin activity by causing its phosphorylation and eventual destruction. Pathological Wnt/β-catenin signaling gets suppressed when this inhibition takes effect. Lower expression of FAT4 leads to improved tumor immune responses through the reduction of PD-L1 expression and abnormal glycosylation.

The LINC01226 acts onotelogically in gastric can-cer by binding with STIP1 protein, which increases HSP90-β-catenin binding affinity. Stimulation of the Wnt/β-catenin signaling pathway has been linked to the progression of gastric cancer, more likely due to higher β-catenin levels (Hua et al., 2023). Research shows that breast cancer cells keep β-catenin stable through RACK1 action, which stops proteasomal breakdown to drive Wnt/β-catenin signaling and cell growth (Ashrafizadeh et al., 2020a). However, nuclear entry of the β-Catenin in colon cancer progression is driven by its disease-causing function, through PECAM-1 mediated endothelial-mesenchymal transition (Wu et al., 2009). Researchers should investigate how β-catenin contributes to diabetic pathology, particularly through its EndMT mechanism. The research indicates that β-catenin presents an opportunity for therapeutic intervention, which could help treat skeletal fluorosis and other conditions in skeletal health. Research by Srivastava and Flora proves that fluoride increases bone metabolism along with osteoblast activities, yet the β-catenin inhibition limits both processes by reducing Runx2 expression (Srivastava and Flora, 2020). These research findings reveal the multiple involvement of β-catenin through different diseases so new therapeutic approaches can now target its pathway (Chu et al., 2020). The research of Chen et al. demonstrated that preactivated osteoblasts increase the favorable bone effects triggered by PTH treatment in diabetic mice resulting in stronger bones with better structure (Chen et al., 2020a, 2020b). Tests conducted by researchers demonstrate how the calcium-sensing receptor (CaSR) binds with Homer1 to activate as a whole through extracellular calcium ion stimulation. Osteoblast cell differentiation depends on the β-catenin stabilization through the AKT activation mechanism, which originates from the mTORC2 complex response to this activation pathway (Rybchyn et al., 2019). Gupta and colleagues discovered that Connexin43 supports Wnt-dependent and independent β-catenin signaling to improve both osteoblast functions and bone metabolism apart from the β-catenin requirements (Gupta et al., 2019). Microfibrillar-associated protein 5 (MFAP5) activates the Wnt/β-catenin pathway to increase β-catenin, phosphorylated GSK-3β, and supports osteoblasts differentiation (Li et al., 2021). The research contributes to establishing fundamental knowledge of the effects that β-catenin can have on skeletal well-being.

THE SIGNALING MECHANISM OF WNT/β-CATENIN

When the Wnt signal fails to activate or the Axin-APC-GSK-3-CK1 receptor complex gets blocked, this complex phosphorylates the cytoplasmic β-catenin, leading to its degradation, which prevents the β-catenin from nuclear translocation (Wiese et al., 2018). The interaction of LRP5/6 receptors and Frizzled (Fzd) with Wnt proteins activates the Dishevelled (Dvl) proteins located inside cells. Once in the membrane, the Dvl proteins interact through their DIX domains with Axin’s DIX domain, which results in Axin relocating from the usual cytoplasmic degradation complex that degrades β-catenin. GSK-3 becomes inefficient in phosphorylating β-catenin because the degradation complex no longer contains Axin at this particular moment. Because of this process, β-catenin builds up in the cytosol where it cannot be broken down by proteasome activity. Large nuclear entry of unbound β-catenin protein decentralizes the LEF and TCF transcription factor-Groucho repressor complex. The β-catenin protein binds with LEF and TCF transcription factors inside the nucleus, where it then attracts crucial cofactors required for transcriptional activation. The Wnt proteins activate transcription factors that trigger elevated gene expression of their target genes (Fig. 1).

Fig. 1.

The Wnt signaling network is broadly divided into the canonical (β-catenin dependent) and non-canonical (β-catenin independent) pathways. In the absence of Wnt ligands, β-catenin levels in the cytoplasm are tightly controlled by a multiprotein “destruction complex” composed of glycogen synthase kinase-3β (GSK-3β), adenomatous polyposis coli (APC), and Axin. Within this complex, β-catenin is sequentially phosphorylated and subsequently targeted for ubiquitination and proteasomal degradation, preventing its nuclear accumulation. Activation of the canonical pathway occurs when Wnt ligands, such as Wnt1 or Wnt3a, bind to frizzled (FZD) receptors together with the co-receptors LRP5/6. This ligand-receptor interaction disrupts the destruction complex, inhibits GSK-3β, and allows β-catenin to accumulate in the cytoplasm. The stabilized β-catenin then translocates into the nucleus, where it interacts with TCF/LEF transcription factors and cofactors such as CBP to activate downstream target genes involved in cell proliferation, differentiation, and survival. In contrast, the non-canonical pathways triggered by ligands such as Wnt5a utilize FZD receptors or FZD/Ror1/2 receptor complexes but function independently of β-catenin. These branches regulate processes including planar cell polarity and intracellular calcium signaling. The extracellular regulation of Wnt signaling is also critical. The co-receptor LRP5/6 contains four β-propeller (BP) domains that serve as Wnt ligand-binding sites. Inhibitors such as Dickkopf-1 (DKK1) and sclerostin can bind to LRP5/6 and block ligand access, thereby suppressing canonical signaling. DKK1 specifically interacts with the BP1 and BP3 domains of LRP5/6 and, in association with Kremen, induces receptor internalization. Sclerostin preferentially binds to the BP1 domain of LRP5/6, and its inhibitory activity is enhanced by interaction with LRP4. Additional modulators further fine-tune signaling. The secreted frizzled-related protein (sFRP) family acts as a decoy receptor by binding Wnt ligands through their cysteine-rich domains, preventing ligand interaction with FZD. The ubiquitin ligases ZNRF3 and RNF43, which are themselves Wnt target genes, mediate degradation of FZD receptors, establishing a negative feedback loop. Conversely, the R-spondin (RSPO) family of secreted proteins enhances signaling by binding to LGR receptors and promoting the degradation of ZNRF3/RNF43, thereby stabilizing FZD and amplifying pathway activity. Through this intricate interplay of activators, inhibitors, and feedback regulators, the Wnt/β-catenin system maintains a delicate balance that is essential for normal tissue development and homeostasis, while its dysregulation underlies diverse pathological conditions.

THE WNT PROTEINS

The secreted glycoprotein family known as Wnt proteins serves as a fundamental element that controls the growth and development of cells (Xiao et al., 2023). The Wnt protein processing requires the O-acyltransferase Porcupine (PORCN) to acetylate Wnt proteins inside the endoplasmic reticulum, followed by Wntless (WLS)-mediated transport through intracellular compartments (Qi et al., 2023). There are two principal Wnt signaling routes at play in biological systems, i.e. the signaling of β-catenin-mechanism functions under the name canonical pathway, and the independent pathways of β-catenin, which include the pathway of Wnt/Ca²⁺ and the polarity of the planar cell pathway (PCP) (Fig. 2). The researchers discovered the initial Wnt1 gene in 1982 during investigations of this widespread group of mammalian Wnt proteins.

Fig. 2.

Canonical Wnt signaling pathway. The canonical Wnt cascade functions in two modes I.e; “off” and “on.” In the absence of Wnt ligands, β-catenin stability is regulated by the multiprotein destruction complex, ensuring its continuous phosphorylation and degradation. Pathway activation occurs when Wnt ligands engage frizzled (FZD) receptors and LRP co-receptors, leading to disassembly of the destruction complex and stabilization of β-catenin. The accumulated β-catenin subsequently translocates into the nucleus, where it associates with TCF/LEF transcription factors to regulate downstream gene expression. Key components include: LRP (low-density lipoprotein receptor-related proteins), Dvl/Dsh (dishevelled), GSK3β (glycogen synthase kinase-3β), CK1α (casein kinase-1α), APC (adenomatous polyposis coli), PP2A (protein phosphatase 2A), β-TrCP (β-transducin repeat-containing E3 ubiquitin ligase), TCF/LEF (T cell factor/lymphoid enhancer factor), TNKS (tankyrases), CBP (CREB-binding protein), VEGF (vascular endothelial growth factor), EGFR (epidermal growth factor receptor), and SOX family transcription factors.

Wnt5a serves as the principal ligand of the non-canonical area in Drosophila melanogaster (Ashrafizadeh et al., 2020a), but the β-catenin-dependent pathway attracts more research focus. Multiple Wnt family proteins exist within the group because each member acts with uniqueness to regulate biological operations which cover growth and development, together with energy metabolism. Additional investigations of these proteins must occur to explore their role in disease development so the findings can support specific treatment plans for affected conditions. The diverse range of Wnt proteins functions distinctively during disease development and medical intervention processes. The tumor disease linkage exists specifically with the Wnt1 protein. Research has verified that the Wnt1 protein inside the cells exhibits positive links with cancer grade and stage development, but membrane-bound Wnt1 presents opposing results with high-grade cancers (Pietrus et al., 2023). More recently, work has shown how mitotic serine-threonine kinase NEK2 participates in cancer progression. Results show that microRNA miR-130a-3p effectively restricts Wnt1 expression, which may establish a therapeutic approach against colorectal tumorous growth. The different forms of Wnt proteins contribute to various cancers (Song et al., 2021). The proto-oncogene Wnt2 functions as a tumor marker that indicates poor prognosis in cases of gastric and colorectal cancers (Yao et al., 2017). The Wnt2 protein, which comes from cancer-associated fibroblasts uses a SOCS3/JAK2/STAT3 signaling pathway to stop antitumor immune reactions (Huang et al., 2022). Embryonic development and neural tube formation require Wnt3 to function properly, while it works as an oncogene in other cellular processes. The protein participates in two distinct genetic conditions, including tetra-amelia and exhibits multiple effects when people get exposed to radiation, where it supports tissue healing at lower doses yet aggravates injuries from higher doses (Yuan et al., 2023). The scientific evidence shows that extended G protein-coupled estrogen receptor stimulation produces enhanced intestinal stem cell multiplication by Paneth cells releasing Wnt3 during the menopausal period (Xiao et al., 2023). The research team discovered that HNF4α functions as an upstream controller for Wnt3 and Paneth cells while advancing our knowledge of intestinal health mechanics (Jones et al., 2023). Wnt proteins function as diverse critical elements across various diseases while demonstrating complex signaling behavior. Future investigation of Wnt protein mechanisms across disease development will enable researchers to develop clinical treatment methods that identify new therapeutic targets to enhance patients’ health outcomes. Two functionally distinct roles of the Wnt-β-catenin signaling pathway in bone homeostasis are defined: it sustains osteoblastic differentiation and proliferation, as well as osteoclast activity control (Table 1). Essentially, the Wnt/β-catenin signaling pathway has an important role in bone homeostasis because its reactions to genetic alterations, environmental contaminants and oxidative damage, as well as stimuli by mechanical load and pharmacological inputs, are complex. Lab studies on ankylosing spondylitis show microRNA 96 increases Wnt signaling since it elevates Wnt1 and β-catenin levels, which stimulate differentiation of osteoblasts and the formation of new bones, according to Ma et al. (2019). Bone health deteriorates in cadmium exposure because the compound reduces Wnt/β-catenin signaling and prevents the differentiation of mesenchymal stem cells (Wiese et al., 2018). Lawsond et al. (2022) confirm that Wnt1 and Wnt7b ligands get activated through mechanical stress, which activates the canonical pathway to increase bone formation. The research field presents conflicting evidence about Wnt ligands because some have shown both osteoclast differentiation blocking properties through β-catenin or cAMP/PKA pathways (Wang et al., 2021) and simultaneously enhance osteoclast activity. These discovery results demonstrate how the Wnt signaling pathway functions to regulate both osteoblasts together with osteoclasts. Research into bone-related therapeutic strategies requires such fundamental knowledge to build foundational approaches that adjust Wnt signaling pathway operations.

Table 1.

The effects of Wnt/β-catenin signaling on osteoclasts and osteoblasts.

Research objective	Changes in signaling of Wnt/β-catenin	Impact on osteogenesis
Cx43	β-catenin	Control of bone metabolism, bone regeneration, and osteoblast activity
miR-96	Wnt1, GSK-3β and β-catenin	Encourages bone growth, osteoblast differentiation
Wnt3a	β-catenin	Suppresses osteoclast differentiation and deactivates NFATc1
CdCl2	Wnt3a, LEF1 TCF1and β-catenin	Inhibition of Osteoblast differentiation
Fluoride	Wnt3a, GSK3β and Runx2	Rises Mice's cancellous bone development
FGF	Fzd1, -2, -7, and -8	Promotes differentiation of osteoblast
MFAP5	GSK3β and β-catenin	Encourages the differentiation of osteoblasts
Mechanical pressure	Wnt1 and Wnt7b	Encourages the development of bone
Homer1 complexes and CaSR	β-catenin	Promotes differentiation of osteoblast
circRNA422	LRP5	Improves osseointegration and encourages osteoblast differentiation
miR-1295p	(Fzd)-4 and β-catenin	Promotes the differentiation of osteoblasts
SNP9921222	Axin1	Manage the development and progression of bone disorders in human osteoblasts
Sp1	Fzd1	Boost osteoblast mineralization and differentiation in vitro
MiR-16-5p	Axin2	Promotes differentiation of osteogenesis
Lrp5A214V	LRP5	Increases the strength and icroarchitecture of bones
RNF146	Wnt3a, Axin and β-catenin	Suppression of osteoblast differentiation and proliferation
CXXC5	Dvl	Osteoblast differentiation inhibition And the formation of bone marrow
USP4	Dvl	Osteoblast differentiation inhibition
Li2CO3	GSK-3	Causes an increase in the differentiation of osteoblasts and a decrease in differentiation of osteoclast
Genistein	APC	Promote osteoblast differentiation
AR28	GSK-3	Encouraging the osteogenic development of endogenous mesenchymal progenitor cells

REGULATION OF LRP5, LRP6, AND β-CATENIN SIGNALING FOLLOWING THE WNT BINDING

The assembly of the protein receptor complexes occurs along the Wnt ligand signaling pathway, whereby some phosphorylation-dependent factors assemble one after another (Wu et al., 2021). The loss of phosphorylation prevents β-catenin from being stabilized as a substrate of GSK3 in a sequence- and reaction-dependent manner. In this process, the phosphorylated PPPSPxS motif of LRP5/6 acts as a direct inhibitor of β-catenin (Wu et al., 2009). Both β-catenin and the GSK molecules are stabilized by the Wnt signal for extended life spans via pulling GSK protein molecules into multivesicular bodies (MVB) (Tian et al., 2023). The essential and most important element to activate the Wnt/β-catenin signaling is composed of the PPPSP motif, which appears five times in the intracellular domain of LRP5 and LRP6. When the intracellular domain removal occurs in LRP6 (Tauriello et al., 2012), the intracellular domain removal of LRP6 blocks the Wnt signaling pathway. When LRP5/6 is missing extracellular components and maintained in the cell membrane by Wnt/β-catenin signaling, the signaling becomes persistent (Mohn et al., 2014). When PPPSPxS peptide is phosphorylated, the signal transduction of Wnt/β-catenin requires PPPSPxS peptide (Chu et al., 2020). Yep, studies have shown that putting a single PPPSP motif onto LDLR causes the Wnt pathway to become fully activated and causes human cells to express the TCF and the β-catenin responsive transcription. Several research investigations show that Wnt signaling involves receptor endocytosis mechanisms. The Wnt3a and DKK1 separately cause the Wnt3a or DKK1-induced LRP6 internalization, leading to β-catenin signaling activation or inhibition. In the internalization process of LRP6, Wnt 3a activates caveolins to initiate the formation of LRP6 at the membrane surface that gets phosphorylated, and Axin proteins are recruited, which modulate β-catenin levels, while the DKK1 uses clathrin to bring LRP6 inside the cells preventing Wnt 3a mediated β-catenin stabilization (Yu et al., 2016). Since diverse studies have given disparate results regarding the role of endocytosis by Wnt receptors in the transmission of Wnt signal (Guil-Luna et al., 2023), it is not clear how clathrin or caveolins play a role. Examinations of receptor endocytosis and trafficking via pharmacological and molecular tools are pleiotropic, with unclear specificity, which seriously impedes the interpretation of the studies done (Wu et al., 2014).

Disheveled (Dvl) is a cytoplasmic phosphoprotein involved in the Wnt/β-catenin signaling pathway (Fig. 3). The Dvl protein is a critical component of this pathway and plays an important role in intracellular signal transmission. Dvl is composed structurally of three conserved domains: the N terminus DIX domain that provides binding to Axin and other proteins, the central PDZ domain containing a hydrophobic cleft that binds several ligands, and the C terminus DEP domain that interacts with the EGL10 and Pleckstrin proteins to connect to receptors (Capurro et al., 2020; Gan et al., 2008). Together, these domains make Dvl a scaffold protein that functions to bridge Frizzled (FZD) receptors to the downstream signaling apparatus to mediate cellular processes that include proliferation, differentiation and survival (Wu et al., 2019). In addition, dvl is not only required for proper cell development and tissue repair, but is also crucial in many disease pathogenic processes. Pai et al. (2019) carried out research that showed that the Wnt coactivator ASPM binds to Dvl-3 in prostate cancer cells to prevent its degradation. This interaction further stimulates Wnt β-catenin transcriptional activity to drive progression from the primary to metastatic stages of tumor. Likewise, Liu et al. (2020) also reported that mutations in human patients with neural tube defects and Dandy-Walker malformations were associated with Dvl mutations. The R633W mutant in Dvl2 of Drosophila and zebrafish impairs the Wnt/β-catenin pathway and causes toxic effects resulting in severe malformations in these embryos (Table 2). The results highlighted the multiplicity of functions of Dvl in all known biological processes and diseases. The spatially and temporally precise Wnt signaling pathways are regulated by a structural domain, but the disruption of its function gives rise to severe developmental abnormalities and disease progression. In the future, further research should involve the elucidation of the mechanisms of interaction of Dvl with other signal-transducing molecules and how these mechanisms can be modulated to obtain targeted therapy in cancer, neurological disorders, and bone diseases.

Fig. 3.

This figure shows the regular activity of Wnt signaling pathways during normal cell cycles, maintaining proper microtubule dynamics as well as proper chromosome alignment during cell division. The Wnt/STOP signaling mechanism takes precedence over Wnt transcriptional control to execute its new regulatory function in human somatic cells. The proper formation of mitotic microtubules together with correct chromosomal separation results from Wnt-mediated protein stabilization events, i.e. the foundational level of Wnt signaling is crucial for the proper assembly of mitotic microtubules, the absence of basal Wnt signaling results in improper formation of mitotic spindles and chromosome misalignment, leading to aneuploidy, and the Wnt/STOP mechanism activates proteins at the G2/M stage to maintain chromosomal integrity in the karyotype.

Table 2.

Synthetic Wnt/β-catenin modulators and their limitations

Compound	Target	Application	Clinical Status	Limitations
Romosozumab	Anti-sclerostin antibody	Osteoporosis	FDA-approved	Cardiovascular risks; potential cancer promotion
DKK-1 inhibitors	DKK-1	Osteoporosis	Preclinica/Phase I	Off-target toxicity
PORCN inhibitors	Block Wnt ligand secretion	Cancer	Clinical trials	GI toxicity; impaired stem cell function
Frizzled antibodies	Block Wnt-FZD binding	Cancer	Clinical trials	Lack of selectivity; immune effects
β-catenin/TCF disruptors	Transcriptional inhibition	Cancer	Preclinical	Poor pharmacokinetics; systemic toxicity

WNT/β-CATENIN IN BONE HOMEOSTASIS

Bone is a metabolically active tissue that undergoes lifelong remodeling through the coordinated actions of osteoblasts, which are responsible for bone formation, and osteoclasts, which mediate bone resorption. This dynamic process maintains structural integrity, mineral homeostasis, and ensures microdamage repair can be repaired. Wnt/β-catenin is one of the many signaling networks that control skeletal modeling, but it is a master regulator of osteoblastogenesis and an important determinant of bone mass. In canonical signaling, Wnts interact with membrane receptors of the FZD and co-receptors LRP5/6. This inhibits the destruction complex of beta catenin, which typically comprises glycogen synthase kinase-3-β (GSK-3-β), adenomatous polyposis coli (APC), casein kinase 1 (CK1) as well as the Axin (Fig. 4). When this complex is inhibited, β-catenin cannot be phosphorylated and degraded and can accumulate in the form of free protein in the cytoplasm and translocate into the nucleus. After entering the nucleus, β-catenin binds with T-cell factor/lymphoid enhancer factor (TCF/LEF) transcriptional factors to induce osteoblast differentiation transcription through induction of osteoblast transcriptional regulators such as runt-related transcription factor 2 (Runx2), Osterix, and alkaline phosphatase (ALP). These gene products stimulate the differentiation of mesenchymal stem cells to form osteoblasts and deposition of mineralised extracellular matrix so as to make the skeleton strong. Wnt/β-catenin pathway also has indirect effects on osteoclastogenesis. Wnt signaling activates osteoprotegerin (OPG) that acts as a decoy receptor to receptor activator of nuclear factor- kB ligand (RANKL). OPG interferes with differentiation of osteoclast precursors by sequestrating RANKL, an effect that suppresses osteoclast-mediated bone resorption. A decrease in Wnt activity, on the other hand, reduces OPG levels and causes a tilt of the RANKL/OPG balance toward osteoclastogenesis and subsequent bone loss. This two-pronged regulatory feature ensures Wnt/beta catenin as a key pit stop in ensuring path towards equilibrium between bone growth and bone resorption. Its significance is further supported by the evidence in genetic and clinical trials. Mutations in LRP5 gene serve as an example of how small changes in Wnt signaling process can lead to a significant change in bone mass. The presence of gain-of-function mutations in LRP5 represents high bone mass mechanisms and the occurrence of the loss-of-function mutation in LRP5 results in osteoporosis-pseudoglioma syndrome which is characterized by the extreme fragility of the skeleton. Likewise, dysregulation of Wnt antagonists in particular has also been linked to osteoporosis. Increased circulating sclerostin, which is produced by the osteocytes, and DKK-1 have been invariably reported in patients with age-related osteoporosis, as well as osteoporosis associated with glucocorticoids. Antagonistic inhibition of these antagonists can reinstate Wnt activity thereby increasing bone density, and this is the basis behind new biologics that target sclerostin, including romosozumab, which has also shown clinical efficacy in preventing fractures.

Fig. 4.

Wnt signaling is a key regulator of cell growth, differentiation, polarity, and tissue maintenance, and it takes two main forms, the canonical (Wnt-proliferative and wound-healing pathways). In the non-canonical form, the Wnt signal does not lead to the accumulation of β-catenin. By contrast, in the canonical pathway, ligands of Wnts dock to Frizzled receptors as well as LRP5/6 co-receptors and result in the inhibition of the catabolic complex of 8-catenin, consisting of APC, Axin, CK1, and GSK3. This leads to accumulation of β-catenin into the cytoplasm and translocation into the nucleus together with TCF/LEF transcription factors thereby activating gene expression of Wnt-responsive elements that are related to cell growth and differentiation. The non-canonical Wnt pathway in contrast does not depend on the stabilization of β-catenin. Rather, it controls cytoskeletal dynamics, mitotic spindle formation as well as cell polarity. The binding act of Wnt leads to the activation of alternative mediators YAP/TAZ that in conjunction with transcription factors TEADs activates the target genes, whereas the mitotic proteins stability maintains the appropriate organization of microtubules during cell division. Cumulatively, these two contrasting branches of Wnt signaling coordinate extracellular signals to precisely regulate gene expression, cytoskeleton reorganization, and cell fate assignments, and altered balance connects these functions to cancer, developmental pathologies, and tissue disorders.

Beyond genetics, mechanical loading and hormonal regulation also intersect with Besides genetics, mechanical loading and hormonal regulation also modify Wnt/β-catenin signaling pathway by way of fine tuning bone remodeling. Exercise upregulates the Wnt ligands and inhibits sclerostin to mediate bone gain, and the lack of estrogen elevates the Wnt antagonists, promoting bone loss during postmenopausal osteoporosis. These observations allow emphasizing the sensitization of Wnt signaling to whole-body and environmental factors, therefore, becoming a modulator of skeletal physiology with a broad scope of action. Collectively, the Wnt/β-catenin pathway serves as a molecular determinant, which directs the outcome of the fate of the bone tissue. Its stimulation promotes bone formation by osteoblasts but inhibits bone resorption by osteoclasts, whereas its suppression promotes skeletal destruction (Table 3). The accurate regulation of this pathway is thus critical in skeletal homeostasis, and the imbalance in signaling cascade of this pathway forms the mechanistic base of the pathogenesis of both osteoporotic bone loss and Wnt-mediated tumorigenesis.

Table 3.

Key components of Wnt/β-catenin signaling and their roles in osteoblasts and cancer

Component	Function in Wnt/β-Catenin Pathway	Known Role in Osteoblasts	Role in Cancer Progression
Wnt ligands	Secreted glycoproteins that bind Frizzled/LRP5/6 receptors to initiate signaling	Promote osteoblast differentiation, proliferation, and survival	Aberrant secretion promotes tumor growth and metastasis
Frizzled (FZD) receptors	Transmembrane receptors that recognize Wnt ligands	Critical for osteoblast precursor activation	Overexpression linked with oncogenic Wnt activation
LRP5/6 co-receptors	Co-receptors that bind Wnt and activate downstream signaling	Essential for bone accrual; mutations in LRP5 cause low/high bone mass phenotypes	Dysregulation contributes to cancer cell proliferation
Dishevelled (DVL)	Intracellular transducer transmitting Wnt signals to inhibit β-catenin degradation	Enhances osteoblastogenesis by stabilizing β-catenin	Overactivation promotes tumor progression
GSK-3β	Kinase in β-catenin destruction complex; phosphorylates β-catenin for degradation	Inhibits osteoblast differentiation when overactive	Loss of GSK-3β control allows β-catenin accumulation and tumorigenesis
CK1	Kinase initiating β-catenin phosphorylation at destruction complex	Regulates osteoblast development indirectly	Mutations/dysfunction contribute to abnormal signaling in cancers
Axin	Scaffold protein of the destruction complex (with APC, CK1, GSK-3β)	Controls β-catenin turnover; deficiency increases osteoblast activity	Mutations destabilize complex or β-catenin accumulation in cancers
APC	Tumor suppressor protein in destruction complex, recruits β-catenin for degradation	Indirect regulator of osteoblast activity through β-catenin turnover	Loss-of-function mutations strongly associated with colorectal cancer
β-catenin	Central effector; translocates to nucleus to activate TCF/LEF-mediated transcription	Promotes Runx2 expression, osteoblast proliferation, bone formation	Aberrant nuclear accumulation drives oncogenesis and metastasis
TCF/LEF	Transcription factors activated by nuclear β-catenin	Regulate osteoblast-specific gene expression (e.g., osteocalcin, Runx2)	Activate oncogenes like c-Myc, Cyclin D1
Sclerostin (SOST)	Wnt antagonist secreted by osteocytes	Inhibits osteoblast differentiation; suppresses bone formation	No direct cancer link but important in bone metastasis context
DKK-1	Wnt antagonist binding LRP5/6	Inhibits osteoblastogenesis, contributes to osteoporosis	Overexpression in tumors enhances bone metastasis and immune evasion

WNT/β-CATENIN DEFICIENCY AND OSTEOPOROSIS

Osteoporosis refers to progressive skeletal disease that is characterized by low bone mineral density, skeletal microarchitectural deterioration, and an increased risk of bone fragility fractures. Several molecular mechanisms that contribute to osteoporosis include inhibition of Wnt/β-catenin signaling which diminishes the ability of osteoblasts to differentiate. When the stimulation is not adequate, Wnt activity triggers the breakdown of β-catenin through the destruction complex, and osteoblast specific transcription through Runx2 and Osterix cannot take place. These lead to impaired osteogenesis, poor production of the extracellular matrix, and poor bone strength. Osteoblasts deliver three main roles, including: creating new bone tissue, strengthening existing bone mass, and repairing bone damage, with their role in bone metabolic processes (Ponzetti and Rucci, 2021). Bone stability relies on osteoblastic cells producing continuous new bone tissue to maintain their stability and health. Increasing osteoblast production and activity helps build stronger bones and lowers fracture risk to better treat osteoporosis symptoms, according to Martínez-Reina et al. (2021). Therefore, understanding how osteoblasts transform into new cells is vital to developing treatments against and managing osteoporosis. Osteoblast differentiation includes many complex regulatory steps through multiple signaling pathways, which primarily mimic activities from the BMP-Smad and signaling networks of Wnt/β-catenin and are critical for various biological processes (Yao et al., 2017). The pathway of Wnt/β-catenin signaling must function properly to develop bone cells because its disruption causes osteoporosis and slows the process of healing of bone fractures (Vlashi et al., 2023). Medical approaches to treat and prevent osteoporosis gain their direction from our knowledge of how osteoblasts differentiate. Research into the Wnt/β-catenin signaling controls both the understanding of how osteoblasts differentiate and provides valuable insights for treating related diseases to create better prevention and treatment approaches. Medical treatments for osteoporosis involve bone resorption inhibitors alongside drugs that stimulate bone growth and anabolic drugs (Tonk et al., 2022).

Endogenous inhibitors of Wnt signaling have an especially notable role in the pathogenesis of osteoporosis. Sclerostin, which is mainly produced by osteocytes, binds to LRP5/6 to inhibit the Wnt ligand-receptor interaction, whereas Dickkopf-1 (DKK-1) blocks co-receptor activation and reduces the stabilization of β-catenin. Increased levels of these antagonists have been repeatedly reported in postmenopausal women, as well as in patients with glucocorticoid-induced osteoporosis and significantly correlate with the degree of bone loss. Genetics studies also support this connection: patients with loss-of-function LRP5 mutations have the most extreme skeletal fragility seen in osteoporosis-pseudoglioma syndrome, where LRP5 patients have unusually high bone mass with a gain-of-function mutation. Of a therapeutic concern, therapy against Wnt antagonists has offered a new therapeutic approach to treating osteoporosis. Reactivation of Wnt/β-catenin signaling can also be achieved in vivo by neutralizing sclerostin with the monoclonal antibody, mosozumab, which caused a significant improvement in bone mineral density and a reduction in the risk of fractures. There are still concerns about the safety of long-term pathway stimulation that must be observed, especially in patients with prior predisposition to cancer, as there is a thin line between modulating pathways.

WNT/β-CATENIN HYPERACTIVATION AND CANCER

In contrast to osteoporosis, wherein the lack of Wnt activity contributes to bone loss, uncontrolled or unregulated Wnt/beta catenin activation is suspected to play a crucial role in tumorigenesis. One of the more prevalent causes of cancer can be found in genetic mutations that interfere with the destruction complex. Cetuximab is known to target PCA mutations, which in up to 80 percent of colon and colorectal cancer cancers, this high percentage because it results in stabilized β-catenin in their constitutive state. Similarly, loss of CTNNB1 (the β-catenin gene) phosphorylation and degradation leads to sustained nuclear localization and transactivation of oncogenic transcriptional activities. These programs involve an upregulation of MYC, CCND1 (cyclin D1), and matrix metalloproteinases (MMPs) that contribute to increased proliferation, survival, angiogenesis, and metastatic disease. In addition to its inherent genetic mutations, disrupted Wnt signaling can also be mediated through tumor microenvironment. Wnt ligands released by cancer-associated fibroblasts, immune cells, and inflammatory cytokines promote a pro-oncogenic loop by enhancing signaling in tumor cells. Additionally, the Wnt/β-catenin pathway is also reported to sustain cancer stem cells a subpopulation that causes therapy resistance, tumor recurrence, and metastasis. β-catenin facilitates self-renewal and inhibits differentiation of cancer stem cells thus, conferring an advantage to the cancer stem cells overcoming chemotherapy or radiatory treatments. The Wnt/β-catenin has become an area of interest in therapeutically because of its pivotal role in cancer biology. Investigational agents are porcupine (PORCN) inhibitors to inhibit Wnt ligand secretion, monoclonal antibodies against Frizzled receptors, and small molecules to disrupt the β-catenin-TCF/LEF transcriptional complex. Although the results of preclinical studies are promising, clinical translation has been hindered by dose-limiting toxicities, off-target effects, and the risk of disrupting physiologic bone remodeling. These two effects represent the pleiotropic activities of the pathway in both normal and cancerous cells, which underscores how difficult medical modulation of the pathway is likely to be. Overall, these findings identify the paradoxical relationship between Wnt/β-catenin signaling and oncogenesis: its inhibition leads to the occurrence of osteoporosis, whereas its excessive stimulation contributes osteoporosis. This opposition poses a therapeutic dilemma to the drug development process, with the interventions that are beneficial at one context, being a detrimental intervention in the other context. Comprehending such duality preconditions the following debate on the therapeutic quandary and the role as well as need to identify precision modulators (having the potential to regulate within the context deemed as safe), including natural products.

THE THERAPEUTIC DILEMMA

The multipurpose nature of Wnt/β-catenin signaling in skeletal physiology and cancer development is one of the most prominent pesudoparadoxes of current health and cancer management. On the one hand, underdeveloped Wnt activity leads to the development of osteoporosis by inhibiting the differentiation of osteoblasts and stimulating bone resorption; on the other hand, excessive or uncontrolled activation increases both the speed of tumor formation and its development. This poses a medical dilemma in which a treatment that is meant to address one of the pathological states would interfere with another. Enhancement of Wnt signaling would be an exciting approach to treating osteoporosis, specifically with romosozumab, an FDA-approved monoclonal antibody against sclerostin. Clinical trials showed great results in raising bone mineral density and small to record absolute reductions in vertebral and nonvertebral fractures. Nevertheless, cardiovascular adverse events have been a concern, and the risk of Wnt-mediated oncogenic activation precludes long-term use. Furthermore, unregulated Wnt activation in bone can disrupt the dynamic inherent in bone turnover resulting in pathological bone formation that creates low quality bone, despite their elevated density. In oncology, experimental therapies have been concentrated on Wnt/β-catenin inhibition in attempts to halt tumorigenesis. PORCN inhibitors based on small molecules, Frizzled receptor antibodies and β-catenin-TCF disrupting compounds are in development. Although these approaches have shown to be preclinically efficacious, their clinical use has been hampered due to toxicity and nonselectivity. Since Wnt signaling is also critical to normal stem cell maintenance, tissue repair, and immune regulation, then the off-target effects of the broader inhibition of the Wnt pathway have been demonstrated to cause severe side effects like gastrointestinal toxicities, delayed wound healing process, and predisposition to loss of bone. This risk-benefit pairing illustrates how challenging it is to disrupt such a fundamental pathway without also interfering with normal physiology. The therapeutic dilemma ultimately stems from the pleiotropic nature of Wnt/β-catenin signaling. Unlike pathways with more tissue-restricted functions, Wnt is ubiquitously involved in development, regeneration, metabolism, and disease. Thus, systemic activation or inhibition rarely achieves disease-specific benefits without collateral effects. Clinical experience with both anabolic osteoporosis drugs and anticancer Wnt inhibitors underscores the need for context-dependent modulation that can selectively enhance or suppress signaling in diseased tissues while sparing normal ones. The current challenge needs new solutions that were not common in pharmacology. Methods that are in development include focused drug delivery systems, cell specific antibodies, and combination therapeutics that balance minimizing off-target activity. More focus recently has been placed on natural compounds and phytochemicals that have more moderate potency and act on many of the pathway nodes. Such a polypharmacology can potentially enable a more precise control of signaling amplitude than high-affinity synthetic drugs with a single target. Countering the imbalance with these substances but without turning the pathway fully on or off, these agents offer the prospect of safer long-term treatment of conditions such as osteoporosis and cancer.

NATURAL COMPOUND AS MODULATORS OF WNT/β-CATENIN SIGNALING

Precise control of Wnt/β-catenin signaling pathway regulation remains essential for resolving healthcare needs in osteoporosis treatment and bone repair (Fig. 5). Modern medical research examines skeletal health using Wnt/β-catenin, which functions as the fundamental signaling event in bone biology. The precise regulation of this pathway directly affects both osteoblast activity and osteoclastogenesis, as well as determines how bone tissue will remodel (Lin et al., 2024). This pathophysiological disruption produces unregulated bone remolding, which causes degenerative bone conditions. The preservation of homeostasis in this pathway proves critical because it supports healthy bones and produces optimal results during the treatment of bone diseases. Modern scientific research emphasizes the evaluation of natural bioactive compounds which strengthen Wnt/β-catenin signaling pathway. The ability of these compounds to control cell functions without synthetic chemical side effects makes them highly interesting for scientists. Irisin stands out as an important compound because it works as a hormone-like myokine substance in organs including the myocardium, as well as the liver and adrenal glands, and thyroid, together with the central nervous system and white adipose tissue, during physical exercise. The hormone irisin promotes β-catenin expression, leading to better osteoblast differentiation and new bone development. Irisin displays a special impact on tissue health because of its active influence during conditions without enough mechanical stress, like spaces where bone cell perspectives normally decline. Furthermore, irisin has been known to promote β-catenin accumulation as well as to upregulate key osteogenic marker genes, including alkaline phosphatase (ALP) and collagen type I alpha 1 (ColIα1), thus contributing to its role in bone tissue regeneration (Chen et al., 2020a, 2020b). These findings are consistent with the notion that irisin enhances osteogenesis by a strong enhancer of the Wnt/β-catenin signaling. Also, other bioactive molecules such as DCEQA have been shown to potentiate Wnt signaling through upregulating Wnt10a and Axin proteins and upregulating β-catenin phosphorylation. The series of molecular events here leads to differentiation and maturation of precursor cells into osteoblasts and is involved in bone tissue formation and repair. In light of the worldwide increase in incidence of osteoporosis and associated fracture complications, a thorough understanding of the molecular interactions as well as the potential therapeutic value of compounds modulating the Wnt/β-catenin pathway has high biological importance in bone research. Given this, the integration of naturally derived agents, such as irisin, into a therapeutic strategy has great precedence in regenerative medicine and orthopedic care.

Fig. 5.

The Wnt signaling pathway controls both osteoclasts and osteoblasts, through which it shapes bone formation and resorption operations. New bone formation in osteoblasts receives support through mechanisms that enable osteoblast activity by activation of the classical β-catenin-dependent Wnt signaling pathway. Bone resorption reduction happens through reduced osteoclast differentiation because of higher OPG gene expression. The expression of LRP5/6 increases through pathways that do not depend on β-catenin, which strengthens osteoblast differentiation. Wnt5a activates RhoA through ROR2 receptors enabling the differentiation process of osteoblasts. Wnts receive activation through the PLC/PKCδ signaling pathway as it advances both osteoblast differentiation and the process of new bone tissue formation. The OPG expression that occurs through classical Wnt signaling leads to reduced bone resorption in osteoblasts, but non-classical Wnt direction accelerates bone resorption. Through Wnt5a-ROR2 activation, the signaling cascade increases RANKL-mediated osteoclastogenesis by activating c-Jun, which raises RANK expression. The Daam2 aptamer protein activates Rho with adaptive mechanisms that trigger the subsequent activation mechanism via Pkn2 effector kinase. The Pkn3 kinase develops actin rings by binding with c-Src kinase, thus promoting enhanced bone resorption. The activation of NF-kB and NFATc1 by RANKL stimulation becomes inhibited through Wnt4 and Wnt16 Wnt proteins. The activation mechanism stops osteoclast differentiation within appropriate levels to keep bone remodeling processes in equilibrium..

Euodia sutchuenensis Dode contains medicinal properties that help effectively alleviate headaches and gastritis, along with dermatitis. Research confirms that geranyl furanocoumarins present in Euodia sutchuenensis Dode possess anti-mold properties. Studies indicate that Geraniin enhances the capabilities of osteoblast cells through this particular activation mechanism. Chinese Medical herb Astragalus membranaceus demonstrates traditional healing properties that fight cancer growth, reduce inflammation and act as an antioxidant. Scientific evidence demonstrates that Astragalus successfully stops bone loss from occurring in ovariectomized female mice. The main ingredient, Astragaloside I prompts osteoblastic differentiation because it strengthens the Wnt/β-catenin signaling pathway through elevated expression of β-catenin and Runx2 proteins, according to Xun Cheng and his team (Cheng et al., 2016). The natural compound Bergamottin, which resides mostly in citrus fruits, shows two significant biological actions by stopping adipogenesis while functioning as a cancer cell antioxidant. Bergamottin induces osteoblast differentiation through the Wnt/β-catenin signaling mechanism by promoting LRP6/Wnt3a/β-catenin expression alongside decreasing GSK-3β expression as Wang and colleagues have shown recently. The Wnt/β-catenin signaling mechanism becomes active when exposed to FO because β-catenin expression increases, thus promoting osteogenesis and enhancing ALP activity as well as mineralization capacity in osteoblasts. Queensland sugar contains Polygonatum sibiricum polysaccharide (PSP) that demonstrates anti-inflammatory properties and diminishes amyloid-β-related toxicity toward neural cells. The PSP treatment method enhances mesenchymal stem cell osteoblast differentiation and mineralization potential with increased ALP activity, according to Du et al. (2016). The process leads to increased COL I expression and genes that activate ALP production.

After PSP exposure, the expression, along with activation of β-catenin, increases, which leads to a higher nuclear concentration of β-catenin molecules. The nuclei-acquired β-catenin molecules activate Wnt/β-catenin signaling by binding with TCF/LEF, which promotes both osteoblast differentiation and function (Du et al., 2016). The phytoestrogen group in soybeans, called soybean isoflavones (SI), exhibits several biological characteristics that involve antioxidant protection, together with anti-inflammatory responses and tumor prevention, while it supports lipid regulation and maintains bone density (Cederroth et al., 2010). The research of Fang Yu and colleagues exhibited that SI enhances Wnt3a and β-catenin protein expressions to activate the Wnt3a/β-catenin signaling pathway for promoting osteoblast differentiation (Yu et al., 2015). Reputable research validates that the natural hydroquinone derivative arbutin found in bearberry leaves protects against skin damage and offers anti-inflammatory protection.

Among the compounds found in Astragalus membranaceus stands out Astragaloside I (As-I). Research shows Bergamottin controls Wnt/β-catenin signaling by increasing LRP6, Wnt3a, and β-catenin while it decreases GSK-3β expression for osteoblast differentiation and osteoporosis-linked bone loss control (Wang et al., 2022a, 2022b). The research conducted by Devalaraja et al. (2011) established that Psidium guajava possesses medical capabilities for treating diabetes alongside obesity and osteoporosis. Cellular processes, including proliferation, differentiation, and apoptosis, are governed via the Wnt/β–catenin signaling pathway. However, this pathway is also responsible for the development of several serious health conditions, including different forms of cancer, fibrotic diseases and neurodegenerative disorders, but when this pathway is chemically interrupted or dysregulated, this can lead to the development of these aforesaid diseases. In most cases, this pathway is aberrantly activated, which results in the accumulation of β-catenin in the cytoplasm and its translocation to the nucleus, where it starts transcription of oncogenes along with other deleterious cellular events. Based on this, therapeutically modulating the Wnt/β-catenin pathway has become a major area of current biomedical research. Recently, it has been shown that naturally occurring bioactive compounds have attracted much attention for their potential to regulate and modulate this signaling cascade. Alternative therapeutic avenues with less toxicity and fewer side effects than synthetic drugs are provided by these natural agents. As pointed out by Ge et al. (2023), several natural compounds are known that effectively interfere with the Wnt/β-catenin pathway at multiple molecular checkpoints (Fig. 6). Among them are mechanisms, for example, the inhibition of key pathway components, destabilization and enhanced degradation of β-catenin protein, suppression of Wnt-responsive gene expression. For example, a polyphenolic compound, curcumin, derived from turmeric plant, inhibits this pathway in two different ways. In addition, it accelerates the degradation of β-catenin and represses the expression of downstream Wnt target genes in tumorigenesis. Similarly, the polyphenol resveratrol, present in grapes and red wine, has been shown to stabilize β-catenin under certain conditions, thus promoting its activation of target genes that control a healthy form of cell differentiation. The most valuable aspect of this property of resveratrol is that it is very useful in regenerative medicine and tissue engineering, where cell fate is to be regulated in a controlled manner. Furthermore, other natural agents like vitamin D and Forskolin also exert controlling action on the Wnt/β-catenin signaling cascade. Specifically, vitamin D suppresses β-catenin activity, and therefore limits the growth of abnormal cells, while forskolin, which indirectly affects Wnt pathway components, through cAMP signaling. These results indicate that a large diversity of natural chemicals may serve as a source of therapeutics to repair Wnt/β-catenin signaling that could be applied to the treatment of chronic disease, cancer, and tissue repair.

Fig. 6.

Proposed mechanisms highlighting the anticancer effects of selected dietary phytochemicals. (A) Modulation of the PI3K/Akt/mTOR signaling cascade, (B) Regulation of the Ras–Raf–MEK–ERK pathway, and (C) Inhibition of the JAK/STAT3 signaling axis. Akt, protein kinase B; CDK, cyclin-dependent kinase; EGCG, epigallocatechin gallate; ERK, extracellular signal-regulated kinase; JAK, Janus kinase; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; Raf, rapidly accelerated fibrosarcoma; Ras, rat sarcoma; STAT3, signal transducer and activator of transcription.

Natural compounds reveal multiple methods to regulate Wnt/β-catenin signaling, where they primarily focus on different elements of this signaling cascade. Curcumin, a diarylheptanoid isolated in the rhizome of Curcuma longa, is one of the most studied agents. Mechanistically, curcumin disrupts the activity of GSK-3β, stabilizing β-catenin in osteoblast cells and enhancing differentiation, bone matrix mineralization, and increase bone density. Meanwhile, Curcumin plays a suppressive role in cancer cell in a dependent context. In breast cancer, curcumin has been reported to inhibit progression, trigger apoptosis, prevent movement, and invasion, whereas in colorectal cancers, it suppresses the expression of the oncogenic Wnt targets like Cyclin D1 and c-Myc. Several phase I-III clinical trials have tested curcumin in patients with metastatic and advanced colorectal cancers but results indicate favorable tolerability but its deficient systemic absorption and insufficient systemic bioavailability are pertinent issues. This has seen the advent of novel delivery systems, such as liposomal formulations and polymeric nanoparticles, to improve its usefulness as an osteogenic enhancer and an anticancer drug. The other compound of great importance is genistein, which is an isoflavone that is mainly found in soy products. Genistein exerts regulation on the Wnt/β-catenin pathway by preventing Akt phosphorylation and stimulating GSK-3β dephosphorylation, resulting in 3 induced phosphorylation and subsequent proteasomal destruction of β-catenin. This two-pronged action leads to repression of oncogenic Wnt targets in prostate, breast and colorectal cancer cells. Besides its anti-proliferative and pro-apoptotic properties, genistein has been found to have a synergistic effect when used in combination with conventional chemotherapy, e.g., FOLFOX or FOLFOX-Avastin protocol, and is subjected to clinical trials in patients with metastatic colorectal cancer. At a skeletal level, genistein promotes osteoblast differentiation and mineralization, an aspect that demonstrates its capacity to be a selective regulator of pathways that can be used beneficially in both the bone and cancer context.

Resveratrol, a stilbene found in grapes, blueberries, and peanuts, is another natural compound that exhibits a finer control of Wnt/β-catenin signaling. In osteogenic conditions, resveratrol improves stabilization of β-catenin and increases Runx2 transcription-based matrix formation. On the other hand, in cancer models, it inhibits β-catenin/TCF transcription, potentiates E-cadherin, and Wnt-1 oncogenic signaling. Its antiproliferative, pro-apoptotic, and anti-metastatic action in colorectal, breast, and lung cancer is consistently reported in the experimental literature. In patients with established colon cancer, phase I clinical trials showed that resveratrol was well tolerated, but low levels were found in the blood because of low levels of bioavailability. This evidence highlights the translational potential of resveratrol and the key importance of delivery systems that overcome its pharmacokinetic shortcomings. Quercetin, a naturally occurring flavonoid found in fruits and vegetables, is also known to regulate the Wnt/β-catenin pathway via a variety of molecular actions. It prevents the attachment of β-catenin to TCF, as well as blocks the activity of GSK-3β and increases the instance of E-cadherin, which lost the invasive capability in malignant cells. Quercetin has shown robust anticancer effects in colorectal, breast and hepatic cancer models but there are limited human clinical trials that target the Wnt pathway. In the bone-related sceneries, quercetin has also been described to confer beneficial outcomes on the survival of osteoblasts owing to its antioxidant and anti-inflammatory capabilities, although the extent of its clinical potential remains unrevealed.

Epigallocatechin gallate (EGCG), the major catechin component in green tea, shows the duality of action in osteogenesis and cancer prevention. Mechanistically, EGCG depresses the β-catenin/TCF-4 pathway, and at the same time increases the levels of Wnt inhibitors, including HBP1, sFRPs, and E-cadherin. In preclinical models, EGCG demonstrates a high level of anticancer activity, especially in colorectal, lung, and breast models, as well as on cancer stem cell populations. Despite an abundance of evidence backing other health-related phenomena, the ability of EGCG to therapeutically modulate Wnt signaling is at the very earliest phase of investigation. However, its safety record and dietary prevalence make it a good candidate as a chemopreventive agent. Along with polyphenols and flavonoids, vitamin D and its active metabolite 1 alpha, 25-dihidroxyvitamin D 3 have a significant impact on Wnt/β-catenin regulation. Vitamin D negatively regulates oncogenic pathways by decreasing the activity of the β-catenin/TCF, upregulating DKK1 and E-cadherin. Meanwhile, the interactions of vitamin D receptor (VDR) with β-catenin aid in its bone-protective effects, including the promotion of osteoblast differentiation and mineralization. Clinical evidence has revealed its possible contribution to the prevention of colorectal cancer, as have been determined through double-blind randomized trials, which further highlights its duality in skeletal and cancer biology.

Plants deliver these natural compounds, which show great potential in Wnt/β-catenin pathway management for cancer control and therapeutic methods. Additional research must address bioavailability issues and completely understand their clinical application mechanisms (Table 4).

Table 4.

Natural compounds modulating Wnt/β-catenin signaling in osteoporosis and aancer

Compound	Source (Plant/Species)	Mechanism of Action on Wnt/β-catenin	Effect in Osteoporosis	Effect in Cancer
Icariin	Epimedium brevicornum	Stabilizes β-catenin; enhance in Runx2, ALP	Enhances osteoblast differentiation, enhances BMD	Limited proliferation of cancer cells
Quercetin	Fruits, Vegetables	Suppresses oxidative stress; modulates β-catenin	Promotes bone health	Induces apoptosis via β-catenin inhibition
Apigenin	Parsley, Chamomile	Blocks β-catenin nuclear translocation	Mild osteogenic effect	suppresses c-Myc and cyclin D1, suppresses proliferation
Berberine	Berberis vulgaris	Activates Wnt in bone; inhibits in tumors	Protects against steroid-induced osteoporosis	Induces β-catenin degradation
Harmine	Peganum harmala	β-catenin destabilization	Limited reports	Inhibits hepatocellular carcinoma cell growth
Asiatic acid	Centella asiatica	Promotes β-catenin stabilization	Enhances osteogenesis	Suppresses tumor proliferation
Curcumin	Curcuma longa	Dual: Stimulates bone regeneration; inhibits tumor Wnt signaling	Enhances osteoblastogenesis	Decreses proliferation, invasion in colorectal cancer
Resveratrol	Grapes, Red Wine	Dual: Context-dependent modulation	Enhance bone formation	Suppresses tumor progression and CSC activity

CONCLUSIONS

The Wnt/β-catenin signaling pathway functions as a fundamental developmental factor for the emergence of both osteoporosis and cancer, since pathway abnormalities result in these conditions. The pathway functions decisively to drive osteoblast differentiation and form bones, which presents itself as a future therapy option to build bone density and stop fractures. Medical interventions that regulate this pathway substantially enhance the treatment results for osteoporosis patients and allow them to live better while reducing the complications that stem from the disease. Researchers believe that Wnt/β-catenin signaling shows a promising area for cancer treatment therapy development. Multiple forms of cancer develop from their abnormal activation, so more knowledge about these mechanisms offers potential solutions for developing targeted therapies. These therapeutic strategies block cancer cell proliferation and metastasis because these events represent crucial aspects for tumor growth and spreading control. Scientists utilize advanced technology like gene modification to create accurate biomedical solutions that attack designated areas of this signaling pathway. Studies of the future focus on elaborating our comprehension of regulatory mechanisms which control Wnt/β-catenin signaling pathway operation. The obtained knowledge will be essential for developing safe approaches to treat diseases, including osteoporosis and cancer, while minimizing adverse side effects and health complications. Small drugs, together with natural compounds, demonstrate clinical use of Wnt/β-catenin signaling while providing better care options to treat patients through reduced disabilities and better overall health outcomes. Future research studies indicate that increased examination of Wnt/β-catenin signaling pathway manipulation will potentially result in better treatments. Investigators have established thorough knowledge of this intricate biological approach, which leads to potential medical applications in treating diseases across healing and cancer-related fields.