International journal of dentistry · 2026
Nifedipine Induces FAM20A Upregulation and LRP2/CUBN-Mediated Fetuin-A Accumulation in Gingival Overgrowth.
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De la Rosa Isaac, Baker Amina, Cannaya Vidjeacoumary, Rodríguez-Cavallo Erika, Méndez-Cuadro Darío, Plazas-Roman Jaime, Simancas-Escorcia Víctor, Diaz-Caballero Antonio, Kozyraki Renata
Аннотация
AIM: Nifedipine-induced gingival overgrowth (NIGO) has been linked to fibrotic remodeling of the gingiva, yet whether FAM20A and Fetuin-A contribute to this process is unknown. Here we ask whether their expression is altered in NIGO and, if so, whether nifedipine itself drives this change.
MATERIAL AND METHODS: We examined gingival biopsies from 18 patients under long-term nifedipine treatment and 17 unaffected controls by immunofluorescence, western blotting, and RT-qPCR. In parallel, human gingival fibroblasts (hGF) were exposed to 100 ng/mL nifedipine for either 48 h or 7 days to test for direct drug effects on FAM20A, FAM20C, Fetuin-A, alpha-smooth muscle actin (α-SMA), and the endocytic receptors LRP2 and CUBN. Protein expression was graded semiquantitatively, and group differences were considered significant at p < 0.05.
RESULTS: Both FAM20A and Fetuin-A were markedly overexpressed in fibrotic NIGO gingiva. Nifedipine exposure raised FAM20A expression in hGF, yet left Fetuin-A unchanged at either the transcript or protein level-an apparent contradiction that prompted us to examine its receptors, LRP2 and CUBN. These were barely detectable in healthy gingiva but abundant in NIGO tissue, where Fetuin-A colocalized with LRP2; nifedipine reproduced this induction of LRP2/CUBN in cultured hGF. Together, these findings point to enhanced Fetuin-A endocytosis, rather than increased synthesis, as the source of its accumulation in NIGO. TGFβ signaling was not activated under any nifedipine treatment condition tested.
CONCLUSION: FAM20A, Fetuin-A, and the LRP2/CUBN endocytic pair emerge as central molecular players in NIGO. Our data indicate that nifedipine drives FAM20A upregulation and boosts LRP2/CUBN-dependent Fetuin-A uptake through a TGFβ-independent route, offering a new mechanistic view of NIGO and pointing to candidate targets for future therapeutic strategies.
MATERIAL AND METHODS: We examined gingival biopsies from 18 patients under long-term nifedipine treatment and 17 unaffected controls by immunofluorescence, western blotting, and RT-qPCR. In parallel, human gingival fibroblasts (hGF) were exposed to 100 ng/mL nifedipine for either 48 h or 7 days to test for direct drug effects on FAM20A, FAM20C, Fetuin-A, alpha-smooth muscle actin (α-SMA), and the endocytic receptors LRP2 and CUBN. Protein expression was graded semiquantitatively, and group differences were considered significant at p < 0.05.
RESULTS: Both FAM20A and Fetuin-A were markedly overexpressed in fibrotic NIGO gingiva. Nifedipine exposure raised FAM20A expression in hGF, yet left Fetuin-A unchanged at either the transcript or protein level-an apparent contradiction that prompted us to examine its receptors, LRP2 and CUBN. These were barely detectable in healthy gingiva but abundant in NIGO tissue, where Fetuin-A colocalized with LRP2; nifedipine reproduced this induction of LRP2/CUBN in cultured hGF. Together, these findings point to enhanced Fetuin-A endocytosis, rather than increased synthesis, as the source of its accumulation in NIGO. TGFβ signaling was not activated under any nifedipine treatment condition tested.
CONCLUSION: FAM20A, Fetuin-A, and the LRP2/CUBN endocytic pair emerge as central molecular players in NIGO. Our data indicate that nifedipine drives FAM20A upregulation and boosts LRP2/CUBN-dependent Fetuin-A uptake through a TGFβ-independent route, offering a new mechanistic view of NIGO and pointing to candidate targets for future therapeutic strategies.