Nifedipine Induces FAM20A Upregulation and LRP2/CUBN-Mediated Fetuin-A Accumulation in Gingival Overgrowth.

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.