Nanoparticle and nanotopography-induced activation of the Wnt pathway in bone regeneration

Jagannathan, Chitra; Waddington, Rachel Jane; Ayre, Wayne

Abstract

Background and Aims: Recent research has focused on developing nanoparticle and nanotopography-based technologies for bone regeneration. The Wingless-related integration site (Wnt) signaling pathway has been shown to play a vital role in this process, in particular in osteogenic differentiation and proliferation. The exact mechanisms by which nanoparticles and nanotopographies activate the Wnt signaling pathway, however, are not fully understood. This review aimed to elucidate the mechanisms by which nanoscale technologies activate the Wnt signaling pathway during bone regeneration. Methods: The terms “Wnt,” “bone,” and “nano*” were searched on PubMed and Ovid with no date limit. Only original research articles related to Wnt signaling and bone regeneration in the context of nanotopographies, nanoparticles, or scaffolds with nanotopographies/nanoparticles were reviewed. Results: The primary mechanism by which nanoparticles activated the Wnt pathway was by internalization through the endocytic pathway or diffusion through the cell membrane, leading to accumulation of nonphosphorylated β-catenin in the cytoplasm and subsequently downstream osteogenic signaling (e.g., upregulation of runt-related transcription factor 2 [RUNX2]). The specific size of the nanoparticles and the process of endocytosis itself has been shown to modulate the Wnt-β-catenin pathway. Nanotopographies were shown to directly activate frizzled receptors, initiating Wnt/β-catenin signaling. Additional studies showed nanotopographies to activate the Wnt/calcium (Wnt/Ca2+)-dependent and Wnt/planar cell polarity pathways through nuclear factor of activated T cells, and α5β1 integrin stimulation. Finally, scaffolds containing nanotopographies/nanoparticles were found to induce Wnt signaling through a combination of ion release (e.g., lithium, boron, lanthanum, and icariin), which inhibited glycogen synthase kinase 3 beta (GSK-3β) activity, and through similar mechanisms to the nanotopographies. Conclusion: This review concludes that nanoparticles and nanotopographies cause Wnt activation through several different mechanisms, specific to the size, shape, and structure of the nanoparticles or nanotopographies. Endocytosis-related mechanisms, integrin signaling and ion release were the major mechanisms identified across nanoparticles, nanotopographies, and scaffolds, respectively. Knowledge of these mechanisms will help develop more effective targeted nanoscale technologies for bone regeneration.

• Journal Article Type: Review
• Acceptance Date: Sep 20, 2023
• Online Publication Date: Apr 2, 2024
• Publication Date: Apr 30, 2024
• Deposit Date: Dec 7, 2023
• Publicly Available Date: Dec 8, 2023
• Journal: Tissue Engineering - Part B: Reviews
• Print ISSN: 1937-3368
• Electronic ISSN: 1937-3376
• Publisher: Mary Ann Liebert
• Peer Reviewed: Peer Reviewed
• Volume: 30
• Issue: 2
• DOI: https://doi.org/10.1089/ten.TEB.2023.0108
• Public URL: https://uwe-repository.worktribe.com/output/11386832