WNT5A-Associated Osteogenic Enhancement Contributes to the Protective Effects of OPG-Fc in Glucocorticoid-Associated Femoral Head Osteonecrosis.

Authors

Wei Shi, Zeyu Dai, Chaobo Li, Yongqing Xu

Published in

Biomolecules & therapeutics. Volume 34. Issue 6. Pages 1424-1440. Nov 01, 2026. Epub Oct 30, 2026.

Abstract

Steroid-induced osteonecrosis of the femoral head (SONFH) is a progressive orthopedic disorder characterized by an imbalance between bone resorption and bone formation. Although receptor activator of nuclear factor kappa-B ligand (RANKL) blockers are known to suppress osteoclast activity, whether they also promote osteogenesis and the underlying molecular mechanisms remain poorly understood. In this study, we investigated whether osteoprotegerin-Fc (OPG-Fc) exerts osteoprotective effects in SONFH and whether wingless-type MMTV integration site family, member 5A (WNT5A) signaling is involved. A rat SONFH model was established using lipopolysaccharide (LPS) combined with methylprednisolone sodium succinate (MPS), and bone marrow mesenchymal stem cells (BMSCs) were cultured under glucocorticoid-containing conditions. OPG-Fc, the WNT5A antagonist box5, and Wnt5a knockdown were used, and analyses included micro-computed tomography (micro-CT), histological staining, transcriptome sequencing, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and western blotting. Our results demonstrated that OPG-Fc significantly improved bone trabecular microarchitecture, reduced empty lacunae and tartrate-resistant acid phosphatase (TRAP)-positive cells, and increased cartilage thickness in vivo. In vitro, OPG-Fc promoted osteogenic differentiation while inhibiting adipogenic differentiation of BMSCs. Transcriptome and protein analyses revealed significantly higher WNT5A expression following OPG-Fc treatment. Importantly, pharmacological blockade of WNT5A with box5 and Wnt5a knockdown partially attenuated OPG-Fc-associated pro-osteogenic effects, whereas box5 had limited effects on anti-resorptive marker changes. These findings suggest that OPG-Fc exerts dual protective actions in SONFH by suppressing bone resorption and enhancing osteogenic differentiation in association with WNT5A-related signaling. This study provides new mechanistic insights into RANKL blockade therapy and offers a potential molecular target for early intervention in SONFH.

PMID:
42952216
Bibliographic data and abstract were imported from PubMed on 29 Oct 2026.

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