2‐Hydroxyethyl Methacrylate Increases MMP‐1 and MMP‐3 Production in Human Gingival Fibroblasts

ABSTRACT

2‐Hydroxyethyl methacrylate (HEMA), a monomer commonly used in dental resin materials, has been reported to leach from polymerized resins. However, its potential impact on periodontal tissues remains insufficiently understood. This study investigates the effects of HEMA on human gingival fibroblasts (HGFs), which constitute a major component of periodontal connective tissue. Specifically, we examined whether HEMA induces the production of pro‐inflammatory cytokines interleukin‐6 (IL‐6) and interleukin‐8 (IL‐8), as well as matrix metalloproteinases (MMP)‐1 and MMP‐3, which are involved in collagen degradation. Furthermore, we analyzed the intracellular signaling pathways activated by HEMA exposure to elucidate the molecular mechanisms underlying these responses. Cytokine and MMP production were analyzed using the ELISA. In addition, activation of intracellular signaling pathways were examined by Western blot analysis. HEMA treatment did not induce IL‐6 or IL‐8 production, but significantly increased MMP‐1 and MMP‐3 levels in a concentration‐dependent manner. In contrast, tissue inhibitor of metalloproteinases (TIMP)‐1 production was suppressed by HEMA. Moreover, compared with 24‐h exposure, 48‐h exposure induced increases in MMP production and decreases in TIMP‐1 production at lower concentrations of HEMA. Furthermore, HEMA enhanced the phosphorylation of p38 mitogen‐activated protein kinase (MAPK), c‐Jun N‐terminal kinase (JNK), and protein kinase B (Akt). Inhibitor studies revealed that the p38 MAPK, extracellular signal‐regulated kinase (ERK), JNK, and Akt signaling pathways are involved in the regulation of MMP‐1 and MMP‐3 production. These findings suggest that HEMA leaching from resin materials may contribute to periodontal tissue destruction by promoting MMP production in HGFs through activation of specific signaling pathways. Given the potential impact of HEMA on periodontal tissues, it is important to ensure complete polymerization of light‐curable resin materials and thorough removal of excess resin cement. The use of HEMA‐free materials may also be worth considering to minimize biological risks.