WNT5A-Associated Osteogenic Enhancement Contributes to the Protective Effects of OPG-Fc in Glucocorticoid-Associated Femoral Head Osteonecrosis
- 1Department of Orthopedics, The 920th Hospital of Joint Logistics Support Force of PLA, Kunming 650032 Guangzhou 510010 China
- 2Department of Orthopedics, General Hospital of Southern Theater Command of PLA Guangzhou 510010 China
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.
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BibTeX
@article{shi2026wnt5aassociated,
title = {{WNT5A-Associated Osteogenic Enhancement Contributes to the Protective Effects of OPG-Fc in Glucocorticoid-Associated Femoral Head Osteonecrosis}},
author = {Wei Shi and Zeyu Dai and Chaobo Li and Yongqing Xu},
journal = {Biomolecules \& Therapeutics},
year = {2026},
month = nov,
doi = {10.4062/biomolther.2026.087},
url = {https://doi.org/10.4062/biomolther.2026.087},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - WNT5A-Associated Osteogenic Enhancement Contributes to the Protective Effects of OPG-Fc in Glucocorticoid-Associated Femoral Head Osteonecrosis
AU - Wei Shi
AU - Zeyu Dai
AU - Chaobo Li
AU - Yongqing Xu
PY - 2026
DA - 2026/11/01
JO - Biomolecules & Therapeutics
DO - 10.4062/biomolther.2026.087
UR - https://doi.org/10.4062/biomolther.2026.087
AB - 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.
SN - 1976-9148
SN - 2005-4483
ER -