GDF15 induced by compressive force contributes to osteoclast differentiation in human periodontal ligament cells

Orthodontic tooth movement (OTM) is initiated by mechanical force and featured as alveolar bone remodeling. Periodontal ligament cells (PDLCs) are one of the major cell components in periodontium and responsible for the signal transduction during OTM. Up to now, the mechanical stress-induced genetic alteration and mechanotransduction mechanisms in PDLCs still remain not fully understood. In this study, we identified a novel compressive force responsive gene, Growth differentiation factor 15 (GDF15), whose expression transcriptionally increased in human periodontal ligament cells (PDLCs) after exposure to the static compressive force in vitro. Functional analyses proved that GDF15 could promote osteoclast differentiation of the murine macrophage cell line RAW264.7 cells. Molecular investigation uncovered that GDF15 could promote the expression of several pro-inflammatory cytokines and RANKL/OPG ratio in PDLCs, while knockdown of GDF15 impaired their upregulation induced by compressive force. Additionally, administration of recombinant GDF15 protein stimulated the M1-like polarization of RAW264.7 cells and THP-1 induced macrophages. Mechanistically, siRNA-mediated suppression of GDF15 significantly disrupted the nuclear translocation of NF-κB and ERK phosphorylation in response to compressive force. Finally, Yes-associated protein (YAP) was demonstrated to be the upstream regulator of GDF15 in human PDLCs, implying a force-induced YAP-GDF15 regulation mechanism. Overall, these data suggested important roles of GDF15 in the functional modulation of both PDLCs and osteoclast progenitors in response to compressive force, providing novel insights into the molecular mechanism of mechanotransduction during OTM process.