Loads of bone: the critical role of MAPKs in osteoblast signal transduction in response to mechanical stimuli in the alveolar bone

Cells residing in, and on, the calcified periodontal bone matrix experience numerous mechanical stimuli daily. The nature of the mechanical stimuli depends on whether the mechanical triggers are physiological, e.g., arising from masticatory forces, distributed via a healthy periodontal ligament to the alveolar bone, or represent "error-loads", e.g., arising during orthodontic tooth movement or around dental implants. Mechanosensitive osteocytes mediate osteoclast and osteoblast recruitment and activity in the presence of unloading, but "error loads" can directly activate signaling pathways in osteoblasts, thereby directing osteoblast activity and accumulating the bone mass essential for a functional masticatory system. Mitogen-activated protein kinases (MAPKs) play a pivotal role in regulating osteoblast growth, differentiation, and survival. This scoping review investigates which MAPKs are rapidly (within minutes) activated in osteoblasts in response to different types of mechanical stimuli. In the discussion, we tie the activation of MAPKs to altered osteoblast number and activity and the production of signaling factors. Using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we identified studies linking MAPKs, osteoblasts, and mechanical stress. The review included 33 in vitro studies. The findings revealed that extracellular signal-regulated kinases ERK1/2, p38, and JNK were rapidly activated in osteoblasts in response to various mechanical stimuli. Fluid flow forces, representing shear stress such as those present during mastication or orthodontic movement, activated all three MAPK branches. Substrate stretch, applied to simulate strain from mastication, induced a broad spectrum of responses. Hydrostatic pressure, often applied to reflect compression from implant loading or mastication, triggered all known MAPK pathways within an hour. In contrast, more selective stimuli such as low-intensity pulsed ultrasound and hypotonic pressure preferentially activated ERK1/2. Regardless of the stimulus, ERK1/2 was usually, and rapidly activated within minutes. In conclusion, diverse mechanical stimuli, including shear stress, substrate strain, and hydrostatic pressure, frequently, and rapidly, upregulate ERK1/2 signaling in osteoblasts. Given ERK1/2's established role in promoting osteoblast proliferation and differentiation, this early activation may help explain the localized bone formation observed under mechanical loading during orthodontic treatment, dental implant integration, or alveolar bone remodeling.