UBC9-Mediated SUMO Pathway Drives Prohibitin-1 Nuclear Accumulation and PITX1 Repression in Primary Osteoarthritis
Abstract
1. Introduction
2. Results
2.1. SUMO-1 Proteins Accumulate in the Nuclei of OA Articular Chondrocytes and Co-Localize with PHB1
2.2. Is PHB1 Directly SUMOylated or Does It Interact with SUMOylated Partners in Primary OA?
2.3. UBC9-Mediated SUMOylation Promotes Nuclear Accumulation of PHB1 in Primary OA
2.4. UBC9 Overexpression in Mice Induces Structural Joint Alterations Characteristic of Primary OA
2.5. UBC9 Overexpression Impairs Cartilage Integrity and Suppresses Pitx1 Expression in Mouse Knee Joints
3. Discussion
4. Materials and Methods
4.1. Study Design
4.2. Human Primary Chondrocyte Cell Preparation
4.3. Cell Line
4.4. Antibodies and Reagents
4.5. Vector Constructs
4.6. Nuclear and Cytoplasmic Protein Isolation
4.7. Co-Immunoprecipitation Assays
4.8. GST-PHB1 and GST-RanGap1 Purification
4.9. In Vitro SUMOylation Assay
4.10. Immunohistochemistry Analysis
4.11. Immunofluorescence Analysis
4.12. In Silico Analysis
4.13. Animal Model
4.14. Radiographic Evaluation of Knee Joints in the Mice
4.15. Immunohistochemistry of Articular Cartilage
4.16. Safranin-O Staining of Articular Cartilage
4.17. Statistical Analysis
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ATP | Adenosine triphosphate |
BSA | Bovine serum albumin |
C28/I2 | Human chondrocyte cell line |
C57BL/6 | Strain of mice |
CAG | CMV enhancer/chicken β-actin |
CHU | Centre Hospitalier Universitaire |
CIBPAR | Comité institutionnel des bonnes pratiques animales en recherche |
CMV | Cytomegalovirus |
c-Myc | Cellular myc, a family of transcription factors |
CO2 | Carbon dioxide |
CRCHUM | Centre de Recherche Centre Hospitalier de l’Université de Montréal |
DAB | 3,3′-diaminobenzidine |
DI water | Deionized water |
DlacZ | Deleted lacZ gene which encodes b-galactosidase |
DMEM | Dulbecco’s Modified Eagle Medium |
DNA | Deoxyribonucleic acid |
DTT | Dithiothreitol |
E1 enzyme | Ubiquitin-activating enzymes |
E2 | Ubiquitin-conjugating enzyme |
E2F | Family of transcription factors |
EDTA | Ethylenediaminetetraacetic acid |
EGTA | Ethylene glycol tetraacetic acid |
FBS | Fetal bovine serum |
FLAG | Short peptide sequence used to label proteins |
GAG | Glycosaminoglycan |
Gal4 | Galactose-responsive transcription factor |
GAPDH | Glyceraldehyde-3-phosphate dehydrogenase |
GST | Glutathione S-transferase |
IgG | Immunoglobulin G |
JSN | Joint space narrowing |
KCl | Potassium chloride |
Kpn1 | Klebsiella pneumoniae OK8 restriction enzyme |
MgCl2 | Magnesium chloride |
NaCl | Sodium chloride |
NCBI | National Center for Biotechnology Information |
NEM | N-ethylmaleimide |
NES | Nuclear export signal |
NLS | Nuclear localization signal |
NP-40 | Nonidet P-40 |
OA | Osteoarthritis |
p53 | Tumor protein p53 |
PBS | Phosphate-buffered saline |
pCCALL2 | Plasmid Conditional CAG- CAG-βgeo-Lox-STOP-Lox-2 |
pcDNA | Plasmid for cloning, DNA |
PCR | Polymerase chain reaction |
PFA | Paraformaldehyde |
PHB | Prohibitin |
PHB1_NLS | PHB1 construct in with deleted nuclear export signal replaced with a nuclear localization signal |
PHB1_ΔSIM | PHB1 construct lacking the identified consensus SUMO-interacting motif |
PITX1 | Paired-like homeodomain transcription factor 1 |
PML | Promyelocytic leukemia |
PML-NBs | Promyelocytic leukemia-nuclear bodies |
PMSF | Phenylmethylsulfonyl fluoride |
RanGap1 | Ran GTPase-activating protein 1 |
RB | Retinoblastoma protein |
SDS-PAGE | Sodium dodecyl sulfate-polyacrylamide gel electrophoresis |
SEM | Standard error of the mean |
SIM | SUMO-interacting motifs |
SUMO | Small ubiquitin-like modifier proteins |
SUMOylation | Process where SUMO proteins are covalently attached to target proteins |
Tg | Transgenic |
TOM-20 | Translocase of outer mitochondrial membrane 20 |
Tris-HCl | Tris (hydroxymethyl)aminomethane hydrochloride |
U2OS | Cell line from human osteosarcoma |
UBC9 | Ubiquitin-conjugating enzyme 9 |
UBE2I | Ubiquitin-conjugating enzyme E2 I |
WT | Wild type |
Xho1 | Restriction enzyme from Escherichia coli strain that carries Xanthomonas holcicola gene |
[V/I]-[V/I]-x-[V/I] | Sequence valine/isoleucine- valine/isoleucine- unknown- valine/isoleucine |
[V/I]-x-[V/I]-[V/I] | Sequence valine/isoleucine-unknown- valine/isoleucine- valine/isoleucine |
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OA | Matched Non-OA Controls (Trauma Cases) | |
---|---|---|
N | 27 | 4 |
Women/men | 17/10 | 2/2 |
Age | 66 ± 2.8 | 43 ± 13.7 |
Characteristic | UBC9 Group (n = 12) | C57BL/6/Wild Type Group (n = 12) |
---|---|---|
Average Age (Weeks) | 38 ± 1.1 | 33 ± 2.4 |
Sex Ratio (M:F) | 6:6 | 6:6 |
Average Weight (g) | 30 ± 2.1 | 33 ± 2.3 |
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Doucet, R.; Elseoudi, A.; Rostami-Afshari, B.; Elbakry, M.; Taheri, M.; Pellicelli, M.; Picard, C.; Lavoie, J.-F.; Wang, D.S.; Lavigne, P.; et al. UBC9-Mediated SUMO Pathway Drives Prohibitin-1 Nuclear Accumulation and PITX1 Repression in Primary Osteoarthritis. Int. J. Mol. Sci. 2025, 26, 6281. https://doi.org/10.3390/ijms26136281
Doucet R, Elseoudi A, Rostami-Afshari B, Elbakry M, Taheri M, Pellicelli M, Picard C, Lavoie J-F, Wang DS, Lavigne P, et al. UBC9-Mediated SUMO Pathway Drives Prohibitin-1 Nuclear Accumulation and PITX1 Repression in Primary Osteoarthritis. International Journal of Molecular Sciences. 2025; 26(13):6281. https://doi.org/10.3390/ijms26136281
Chicago/Turabian StyleDoucet, Roxanne, Abdellatif Elseoudi, Bita Rostami-Afshari, Mohamed Elbakry, Maryam Taheri, Martin Pellicelli, Cynthia Picard, Jean-François Lavoie, Da Shen Wang, Patrick Lavigne, and et al. 2025. "UBC9-Mediated SUMO Pathway Drives Prohibitin-1 Nuclear Accumulation and PITX1 Repression in Primary Osteoarthritis" International Journal of Molecular Sciences 26, no. 13: 6281. https://doi.org/10.3390/ijms26136281
APA StyleDoucet, R., Elseoudi, A., Rostami-Afshari, B., Elbakry, M., Taheri, M., Pellicelli, M., Picard, C., Lavoie, J.-F., Wang, D. S., Lavigne, P., Gorman, K. F., Elremaly, W., & Moreau, A. (2025). UBC9-Mediated SUMO Pathway Drives Prohibitin-1 Nuclear Accumulation and PITX1 Repression in Primary Osteoarthritis. International Journal of Molecular Sciences, 26(13), 6281. https://doi.org/10.3390/ijms26136281