Academic Journal
PDK4 knockdown suppresses osteoclast differentiation in osteoporosis through glycolytic flux suppression and AMPK activation.
| Τίτλος: | PDK4 knockdown suppresses osteoclast differentiation in osteoporosis through glycolytic flux suppression and AMPK activation. |
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| Συγγραφείς: | Huang Y; Department of Nephrology, Shanghai Eighth People's Hospital, No. 8 Caobao Road, Xuhui District, Shanghai, 200235, China., Zhou R; Department of General Practice, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China., Liang R; Department of Nephrology, Shanghai Eighth People's Hospital, No. 8 Caobao Road, Xuhui District, Shanghai, 200235, China., Shen J; Department of Geriatrics, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China. Electronic address: jamesjp801013@163.com. |
| Πηγή: | Bone [Bone] 2026 Aug; Vol. 209, pp. 117911. Date of Electronic Publication: 2026 Apr 27. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Science Country of Publication: United States NLM ID: 8504048 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-2763 (Electronic) Linking ISSN: 18732763 NLM ISO Abbreviation: Bone Subsets: MEDLINE |
| Imprint Name(s): | Publication: New York : Elsevier Science Original Publication: Elmsford, NY : Pergamon Press, c1985- |
| Ιατρικοί όροι (MeSH): | Glycolysis*/genetics , Glycolysis*/drug effects , Osteoclasts*/metabolism , Osteoclasts*/pathology , Cell Differentiation*/genetics , Cell Differentiation*/drug effects , AMP-Activated Protein Kinases*/metabolism , Osteoporosis*/pathology , Osteoporosis*/metabolism , Osteoporosis*/genetics , Osteoporosis*/enzymology , Pyruvate Dehydrogenase Acetyl-Transferring Kinase*/metabolism , Pyruvate Dehydrogenase Acetyl-Transferring Kinase*/genetics , Gene Knockdown Techniques*, Animals ; Female ; Mice ; Rats ; RAW 264.7 Cells ; Rats, Sprague-Dawley ; Enzyme Activation |
| Περίληψη: | Background: Osteoporosis (OP) is a metabolic bone disorder primarily driven by excessive osteoclast-mediated bone resorption. Metabolic reprogramming, particularly a shift toward glycolysis, is crucial for osteoclast differentiation. However, the key regulators linking metabolism to bone resorption remain incompletely defined. Methods: Bioinformatic analysis identified pyruvate dehydrogenase kinase 4 (PDK4) as a key glycolysis-associated gene in OP. Its role was validated using PDK4-knockdown RAW264.7 cells stimulated with receptor activator of nuclear factor kappa-B ligand (RANKL) and ovariectomized (OVX) rat models treated with PDK4-knockdown lentivirus, with or without the AMP-activated protein kinase (AMPK) inhibitor Dorsomorphin in each setting. Western blot was conducted to assess the expression of osteoclast differentiation markers and glycolysis-associated proteins. Glycolytic flux was determined by measuring glucose uptake, intracellular ATP, and lactate levels. Bone microstructure was evaluated by micro-computed tomography, while osteoclast activity was examined by tartrate-resistant acid phosphatase (TRAP) staining. Results: PDK4 was significantly upregulated in RANKL-induced osteoclasts. PDK4 knockdown suppressed the expression of osteoclast differentiation markers and glycolytic flux in vitro. Mechanistically, PDK4 silencing activated the AMPK pathway. The anti-osteoclastic effects of PDK4 knockdown were reversed by the AMPK inhibitor Dorsomorphin. In OVX rats, PDK4 knockdown ameliorated bone loss, reduced osteoclast activity and markers, and suppressed glycolysis-associated protein expression in femur tissues. These therapeutic benefits were again negated by co-administration of Dorsomorphin. Conclusion: PDK4 knockdown suppresses osteoclastogenesis and OP progression by suppressing glycolysis via activating the AMPK pathway. Targeting the PDK4-AMPK-glycolysis axis presents a novel metabolic strategy for OP treatment. (Copyright © 2026 Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: AMPK pathway; Glycolysis; Osteoporosis; PDK4 |
| Molecular Sequence: | GEO GSE230665 |
| Substance Nomenclature: | EC 2.7.11.31 (AMP-Activated Protein Kinases) 0 (Pyruvate Dehydrogenase Acetyl-Transferring Kinase) |
| Entry Date(s): | Date Created: 20260429 Date Completed: 20260715 Latest Revision: 20260715 |
| Update Code: | 20260716 |
| DOI: | 10.1016/j.bone.2026.117911 |
| PMID: | 42055104 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1873-2763 |
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| DOI: | 10.1016/j.bone.2026.117911 |