Klotho Attenuates Glucocorticoid-Induced Osteoblast Cytotoxicity Via Wnt Signaling Pathway Modulation

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Dexamethasone upregulated non‑canonical Wnt5a and downregulated canonical Wnt3a and β‑catenin, correlating with increased osteoblast cytotoxicity.
Klotho transfection counteracted dexamethasone effects, restoring canonical Wnt signalling and suppressing non‑canonical Wnt5a to reduce osteoblast cytotoxicity.
LiCl as a Wnt activator and assays (Annexin V/PI, qRT-PCR, Western blot) confirmed pathway modulation underlying Klotho's protective effect.

Biochem Genet. 2026 May 20. doi: 10.1007/s10528-026-11390-6. Online ahead of print.

ABSTRACT

Glucocorticoids are commonly prescribed in clinical settings; however, their prolonged use at high doses can adversely affect human health. One significant complication following glucocorticoid therapy is glucocorticoid-induced osteoporosis (GIO), which is second in incidence only to senile osteoporosis. Based on previous research indicating that Klotho alleviates dexamethasone-induced osteoblast cytotoxicity through the NF-kB pathway, we aimed to explore the underlying mechanisms in greater depth. We assessed the impact of Lithium chloride (LiCl), a Wnt pathway activator, on glucocorticoid-induced cell cytotoxicity and viability. Cytotoxicity was specifically quantified by Annexin V/PI flow cytometry. We performed qRT-PCR and Western blotting analyzes to scrutinize the expressions of genes and proteins associated with both canonical and non-canonical Wnt signaling pathways. Dexamethasone treatment induced an upregulation of the non-canonical Wnt ligand, Wnt5a, and a downregulation of the canonical ligand, Wnt3a, along with its downstream marker, β-catenin. Transfection with Klotho counteracted these effects. Klotho has the potential to modulate both canonical and non-canonical Wnt signaling pathways, thereby counteracting osteoblast cytotoxicity induced by glucocorticoids.

PMID:42159852 | DOI:10.1007/s10528-026-11390-6

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