Mechanical stress-induced FGF-2 promotes proliferation and consequently induces osteoblast differentiation in mesenchymal stem cells

Mechanical stimuli serve as crucial regulators of bone mass, promoting bone formation. However, the molecular mechanisms governing how mesenchymal stem cells (MSCs) respond to mechanical cues during their differen-tiation into osteogenic cells remain elusive. In this study, we found that cyclic stretching enhances MSC pro-liferation but does not increase the expression of osteoblast-related genes. We further revealed that this proliferative effect is mediated by fibroblast growth factor 2 (FGF-2), synthesized by MSCs in response to me-chanical stress. Cell proliferation induced by cyclic stretching was inhibited upon the addition of either U0126, an inhibitor of mitogen-activated protein kinase kinase (MEK), or early growth response 1 (EGR1)-targeting small-hairpin RNA (shRNA), indicating the involvement of the extracellular signal-regulated kinase (ERK)/EGR1 signaling pathway. Osteoblast differentiation, evaluated through ALP activity, osteoblast-related gene expres-sion, and mineralization, was stimulated by recombinant human FGF-2 (rhFGF-2) when applied during the proliferation phase, but not when applied during the differentiation stage alone. Our results suggest that FGF-2 indirectly promotes osteoblast differentiation as a downstream effect of stimulating cell proliferation. For the first time, we demonstrate that cyclic stretching induces MSCs to produce FGF-2, which in turn encourages cell proliferation through an autocrine/paracrine mechanism, consequently leading to osteoblast differentiation.

Automated summary

Mechanical stretching enhances MSC proliferation without increasing the expression of osteoblast-related genes. Fibroblast growth factor 2 (FGF-2) mediates this proliferative effect. Recombinant human FGF-2 (rhFGF-2) stimulates osteoblast differentiation as a downstream effect of promoting cell proliferation.