2. Academic Validation
  3. Retinoic acid-related orphan nuclear receptor alpha inhibits adipogenic differentiation of bone marrow mesenchymal stem cells via activating WNT/β-catenin signaling pathway

Retinoic acid-related orphan nuclear receptor alpha inhibits adipogenic differentiation of bone marrow mesenchymal stem cells via activating WNT/β-catenin signaling pathway

  • Eur J Med Res. 2025 Nov 5;30(1):1073. doi: 10.1186/s40001-025-03325-5.
Lei He # 1 2 3,  Zihao Chen # 1 2 3,  Tianwei He # 1 2 3,  Jiawei Di 1 2 3,  Lang Mai 1 2 3,  Ruijue Zhu 1 2 3,  Depeng Wu 1 2 3,  Liangming Zhang 4 5 6
Affiliations

Affiliations

  • 1 Department of Spine Surgery, The Third Affiliated Hospital, Sun Yat-Sen University, No.600 Tianhe Road, Tianhe District, Guangzhou, 510630, Guangdong, China.
  • 2 Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Guangzhou, 510630, China.
  • 3 Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Guangzhou, 510630, China.
  • 4 Department of Spine Surgery, The Third Affiliated Hospital, Sun Yat-Sen University, No.600 Tianhe Road, Tianhe District, Guangzhou, 510630, Guangdong, China. [email protected].
  • 5 Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Guangzhou, 510630, China. [email protected].
  • 6 Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Guangzhou, 510630, China. [email protected].
  • # Contributed equally.
PMID: 41194142 DOI: 10.1186/s40001-025-03325-5
Abstract

Background: The balance between adipogenic and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is essential for maintaining bone homeostasis. This study aimed to investigate the role of retinoid-related Orphan Receptor α (RORα) in the adipogenic differentiation of BMSCs.

Methods: Stable BMSC lines with RORα overexpression or knockdown were established. Adipogenic differentiation was evaluated using Oil Red O staining and by measuring the expression of adipogenic markers, including PPARγ2, LPL, LEP, FABP4, and ADIPOQ.

Results: Treatment with the RORα inhibitor SR3335 significantly promoted adipogenic differentiation, whereas the RORα agonist SR1078 exerted the opposite effect. Similarly, RORα-overexpressing (OE-RORα) BMSCs showed reduced adipogenic differentiation, while RORα knockdown BMSCs exhibited enhanced differentiation at 14 days after induction. During adipogenesis, PPARγ2 expression increased significantly, peaking at day 6 before gradually declining. Overexpression and knockdown of RORα accentuated this downregulation and upregulation, respectively, at days 6 and 12. The adipogenic marker genes lipoprotein Lipase (LPL), Leptin (LEP), fatty acid binding protein 4 (FABP4), and Adiponectin C1Q and Collagen domain containing (ADIPOQ) were markedly downregulated in RORα-overexpressing BMSCs at day 12. Moreover, RORα overexpression enhanced β-catenin nuclear translocation at day 1 post-induction and upregulated downstream Wnt/β-catenin signaling molecules (Axin2, c-Myc, CD44) at day 6. Inhibition of Wnt/β-catenin signaling with XAV-939 effectively reversed the suppressive effect of RORα overexpression on adipogenic differentiation and restored the expression of adipogenesis-related genes.

Conclusion: RORα suppresses adipogenic differentiation of BMSCs, at least in part, by activating Wnt/β-catenin signaling.

Keywords

Adipogenic differentiation; Bone marrow mesenchymal stem cells; Retinoic acid-related orphan nuclear receptor alpha (RORα); WNT/β-catenin signaling pathway.

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