Photobiomodulation-Mediated Modulation of TGF-β/Smad Signaling in Stem Cell–Driven Osteogenesis

Bone regeneration remains a significant clinical challenge as a result of limitations presented by autografts, allografts, and synthetic implants. Mesenchymal stem cells (MSCs) serve as key drivers of osteogenesis as they can differentiate into osteoblasts and osteocytes. This process is, however, regulated by the transforming growth factor-beta (TGF-β) signaling pathway, which can upregulate the Runt-related transcription factor 2 (RUNX2) to promote early proliferation and commitment through canonical Smad signaling, and also inhibit late-stage differentiation to prevent excessive matrix deposition. These responses are refined further by noncanonical pathways. Photobiomodulation (PBM), a noninvasive light-based therapy, has emerged as a promising modulator of stem cell-driven osteogenesis, as it can interact with the TGF-β/Smad pathway. PBM exerts effects on the mitochondria, activating cytochrome c oxidase, increasing ATP production, and generating reactive oxygen species in a controlled manner. This leads to a stimulation of MSC proliferation, migration, and osteogenic differentiation. Emerging evidence from various studies shows that PBM can also modulate TGF-β/Smad signaling by activating latent TGF-β, enhancing Smad phosphorylation, and modulating the noncanonical pathways. However, evidence examining this interaction specifically during MSC osteogenesis are few, and the mechanisms underlying their interaction are incompletely understood. This review, therefore, critically examines existing evidence to elucidate some of these mechanisms for MSC osteogenesis. Although it is promising, challenges still exist in standardizing PBM parameters and conducting targeted studies in clinically relevant three-dimensional models. A clearer understanding of these interactions could provide a basis for future research aimed at advancing noninvasive regenerative strategies for bone defects and osteoporosis.