Feng YAN, Nor Dayana Binti Mohd ALI
Eurasian Journal of Medicine and Oncology - 2026;10(4):1-19
Mechanically induced osteoclast-mediated bone resorption and osteoblast-mediated bone formation are the forces behind orthodontic tooth movement (OTM). Despite independent research on the RANKL/OPG/RANK axis, Wnt/beta-catenin signaling, and BMP signaling, the crosstalk among these pathways in the context of OTM has not been systematically synthesized. The interplay of these pathways in the context of OTM would be crucial in the design of specific biological interventions to maximize the safety and efficacy of treatments. In this review, we mechanistically integrate evidence on the interaction among the RANKL/OPG/RANK axis, Wnt/beta-catenin, and BMP signaling pathways to control osteoclastogenesis and osteoblastogenesis in human, animal, and in vitro OTM systems. We searched three databases (PubMed, Cochrane Library, LIVIVO) in April 2026. Following deduplication (n = 20) using Rayyan artificial intelligence, 58 records were screened through PRISMA in two phases. Inclusion criteria included OTM context, defined signaling pathway research with Wnt and/or BMP crosstalk, molecular/cellular outcome data, English language, and peer-reviewed primary research. Narrative synthesis was conducted across 21 studies. RANKL/OPG regulation was universally reported (21/21 studies). The upstream regulator was Wnt/beta-catenin signaling (16/21), and the central mechanosensory-molecular mediator of force transduction and osteoclastogenesis in the presence of RANKL was sclerostin (11/21). BMP-2 was also identified as a mechanosensitive pro-osteogenic target (5/21). Compression-tension molecular asymmetry was also continuously observed, and the magnitude and duration of forces further influenced the dynamics of RANKL/OPG. The convergent mechanosensing pathways on the same RANKL/Wnt effector module were Piezo1, alpha7 nAChR, Ca2+ oscillations, and sympathetic beta-AR. The RANKL/OPG/RANK axis and Wnt/beta-catenin signaling constitute a highly connected regulatory system that regulates OTM bone remodeling. Sclerostin plays a central mechanosensory role in the translation of force to RANKL-mediated osteoclastogenesis. These results offer a molecular rationale to optimize OTM protocols and design specific therapeutics, especially in patients with impaired bone biology.
