β-Catenin: A Key Molecule in Osteoblast Differentiation

Abstract

β-catenin is a key regulator of osteoblast differentiation, proliferation, and bone homeostasis. Through its interaction with transcription factors such as TCF/LEF, Runx2, and Osx, it coordinates gene expression essential for osteogenesis. The aim of this review is to demonstrate how β-catenin signaling is modulated by various physiological and pathological factors, including mechanical loading, oxidative stress, HIV-1 gp120, fluoride, implant topography, and microRNAs. These factors influence Wnt/β-catenin signaling through different mechanisms, often exerting opposing effects on osteoblast function. By integrating these modulators, we provide a comprehensive view of the dynamic regulation of β-catenin in bone biology. Understanding this complexity may provide insight into novel therapeutic strategies targeting β-catenin in bone regeneration, metabolic bone diseases, and pathologies such as HIV-associated bone loss or osteosarcoma.

Keywords: Wnt signaling; bone; differentiation of osteoblasts; osteoblasts; β-catenin.

Figure 1

β-catenin: molecular structure and organization. The schematic image illustrates the major structural domains of β-catenin, highlighting its interaction interfaces at adherens junctions, in the cytoplasm, and within the nucleus, along with known phosphorylation sites. The human β-catenin polypeptide consists of 781 amino acid residues and is characterized by a central core of 12 armadillo repeats (ARMs) represented numerically in the diagram that serve as key platforms for protein-protein interactions. This domain mediates β-catenin binding to cadherins in the plasma membrane (stabilizing cell–cell adhesion) and transcription factors (e.g., TCF/LEF) in the nucleus, driving expression of osteogenic genes such as Runx2, BMP-2, and ALP. These repeats are flanked by two terminal regions, an NTD and CTD, which contribute to the regulation of β-catenin activity and binding specificity. The N-terminal domain (NTD) contains phosphorylation sites (Ser33, Ser37, Thr41, and Ser45) that regulate β-catenin stability via GSK3β-mediated ubiquitination and proteasomal degradation. The C-terminal domain (CTD) acts as a transactivation domain, interacting with transcriptional coactivators such as CBP/p300 and recruiting chromatin remodeling complexes during the transcriptional activation of Wnt target genes.

Figure 2

Intracellular dynamics of β-catenin. Following synthesis, β-catenin is sequestered at adherens junctions through interaction with E-cadherin, where it also associates with α-catenin, thereby indirectly influencing the organization of the actin cytoskeleton. Release of β-catenin from junctional complexes may occur through kinase-mediated signaling events or through E-cadherin downregulation. Once liberated, excess cytoplasmic β-catenin is rapidly phosphorylated by the destruction complex, targeting it for proteasomal degradation. However, a subset of β-catenin molecules may evade degradation by associating with APC in the cytoplasm, which offers transient protection. Activation of the Wnt signaling pathway inhibits the activity of the destruction complex, resulting in accumulation of cytoplasmic β-catenin. The stabilized protein is then translocated into the nucleus, where it forms complexes with TCF/LEF family transcription factors to initiate the expression of Wnt/β-catenin target genes. In addition to TCF/LEF, alternative nuclear factors can provide DNA-binding platforms for β-catenin, sometimes antagonizing canonical Wnt-mediated transcription. The transcriptional function of β-catenin within the nucleus is further modulated through regulation of its nuclear import and export. Beyond its dual role in structural cell–cell adhesion and nuclear gene regulation, β-catenin may also contribute functionally at the centrosome. Abbreviations: CTTA, C-terminal transcriptional activators; NTTA, N-terminal transcriptional activators (adapted from Valenta et al. [13]).

Figure 3

Schematic representation of the dual cytoplasmic and nuclear functions of β-catenin. On the left, β-catenin contributes to cell–cell adhesion by interacting with cadherins at adherens junctions, linking the cadherin complex to α-catenin and the actin cytoskeleton, thereby maintaining integrity and communication. On the right, upon activation of the Wnt pathway, β-catenin translocates to the nucleus where it cooperates with TCF/LEF transcription factors to regulate the expression of target genes that promote proliferation, differentiation, and extracellular matrix formation. This dual role of β-catenin underscores its importance in coordinating structural adhesion with transcriptional programs.

Figure 4

The canonical Wnt signaling pathway plays multiple roles in osteoblastogenesis, being essential for early osteoblast lineage differentiation and also involved in proliferation, maintenance, and differentiation. Interaction of Wnt with FDZ and LRP5/6 receptors induces a signaling cascade that results in the accumulation of β-catenin in the cytoplasm. β-catenin then translocates to the nucleus, where it activates transcription of target genes for osteoblastogenesis and bone formation (scheme on the right). Osteoblasts are derived from mesenchymal precursor cells, which also give rise to adipocytes, among others. The specification of osteoblast identity is governed by transcription factors such as Runx2 (Runt-related transcription factor 2), Cbfa1, and Osx, which are recognized as key regulators of osteogenic commitment (scheme on the left).