Tofacitinib Regulates Endostatin via Effects on CD147 and Cathepsin S
Abstract
:1. Introduction
2. Results
2.1. Tofacitinib Inhibits Angiogenesis in the Co-Culture and Oppositely Regulates MMP-9 and Proteasome 20S Activities
2.2. The Effects of Tofacitinib on Endostatin Are Partly Mediated by CD147
2.3. Tofacitinib Inhibits CD147 Expression through STAT3 and miR-146a-5p
2.4. Tofacitinib Reveals the Activity of Another Protease That Cleaves Endostatin
2.5. Tofacitinib Does Not Affect Col18A Transcription or Deposition but Inhibits the Degradation of Endostatin in Co-Cultures
2.6. Cathepsin S Degrades Endostatin and Tofacitinib Inhibits This Degradation and Extends the Half-Life of Endostatin
2.7. Tofacitinib Reduces Angiogenesis in RA Patients
3. Discussion
4. Materials and Methods
4.1. Cultured Cells
4.2. Sandwich Enzyme-Linked Immunosorbent Assay (ELISA)
4.3. Reducing CD147 Expression by siRNA
4.4. Wound Assay
4.5. Tube Formation Assay
4.6. Quantitative Real-Time PCR (qPCR)
4.7. Western Blot Analysis
4.8. Proteome Profiler Human Protease Array
4.9. MMP-9 Activity Assay
4.10. Proteasome 20S Activity Assay
4.11. Cathepsin S Activity Assay
4.12. Preparation of the De-Cellulararized Extracellular Matrix (ECM)
4.13. Study Population
4.14. Statistical Analyses
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Control | RA Group | p Value | Non-Responding * | Responding * | p Value | |
---|---|---|---|---|---|---|
Number of participants | 25 | 20 | - | 3 | 11 | |
Sex: Female (%) | 19 (95%) | 17 (85%) | ns | 3 (100%) | 10 (91%) | ns |
Age (years) ± SD | 51.44 ± 2.10 | 65.1 ± 6.05 | 0.0007 | 80 ± 3.8 | 63.91 ± 3.7 | 0.0385 |
Body Mass Index (BMI) ± SD | 26.56 ± 1.19 | 27.5 ± 1.09 | ns | 25.13 ± 2.5 | 27.47 ± 1.5 | ns |
Disease duration (years) ± SD | - | 9.9 ± 1.9 | - | 22.0 ± 9.0 | 8.2 ± 2.01 | ns |
Tobacco use (%) | 3 (15%) | 4 (20%) | ns | 0 (0%) | 2 (18.2%) | ns |
Alcohol use (%) | 7 (35%) | 0 (0%) | 0.0123 | 0 (0%) | 0 (0%) | ns |
RF factor (%) | 0 (0%) | 17 (40%) | 0.0017 | 1 (33.3%) | 3 (27.3%) | ns |
CRP ± SD | - | 1.534 ± 0.33 | - | 0.29 ± 0.26 | 1.53 ± 0.43 | 0.0385 |
Comorbidities | ||||||
Hypertension (%) | - | 10 (50%) | - | 2 (66.6%) | 7 (63.6%) | ns |
Hyperlipidemia (%) | - | 5 (25%) | - | 1 (33.3%) | 3 (27.3%) | ns |
Diabetes mellitus (%) | - | 4 (20%) | - | 0 (0%) | 3 (27.3%) | ns |
Medication (at baseline) | ||||||
Methotrexate (MTX) | - | 20 (100%) | - | 3 (100%) | 11 (100%) | ns |
Leflunomide (LEF) | - | 1 (5%) | - | 0 (0%) | 1 (9.1%) | ns |
Sulfasalazine (SSZ) | - | 1 (5%) | - | 0 (0%) | 1 (9.1%) | ns |
Hydroxychloroquine (Plaquenil-PLQ) | - | 3 (15%) | - | 0 (0%) | 3 (27.3%) | ns |
Corticosteroid (%) | - | 3 (15%) | - | 0 (0%) | 2 (18.2%) | ns |
Spearman r | 95% CI | p Values | |
---|---|---|---|
Endostatin | −0.1499 | −0.469 to 0.203 | ns |
MMP-9 | −0.0871 | −0.423 to 0.268 | ns |
TIMP-1 | 0.6159 | 0.342 to 0.793 | 0.0001 |
CRP | 0.7482 | 0.492 to 0.885 | <0.0001 |
TJC | 0.4659 | 0.136 to 0.703 | 0.0063 |
SJC | 0.6656 | 0.409 to 0.825 | <0.0001 |
CDAI | 0.5259 | 0.186 to 0.753 | 0.0034 |
DAS28 | 0.5805 | 0.246 to 0.791 | 0.0015 |
MMP-9 activity | 0.6529 | 0.395 to 0.815 | <0.0001 |
Proteasome 20S activity | −0.6196 | −0.796 to −0.347 | <0.0001 |
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Zisman, D.; Sabtan, H.; Rahat, M.M.; Simanovich, E.; Haddad, A.; Gazitt, T.; Feld, J.; Slobodin, G.; Kibari, A.; Elias, M.; et al. Tofacitinib Regulates Endostatin via Effects on CD147 and Cathepsin S. Int. J. Mol. Sci. 2024, 25, 7267. https://doi.org/10.3390/ijms25137267
Zisman D, Sabtan H, Rahat MM, Simanovich E, Haddad A, Gazitt T, Feld J, Slobodin G, Kibari A, Elias M, et al. Tofacitinib Regulates Endostatin via Effects on CD147 and Cathepsin S. International Journal of Molecular Sciences. 2024; 25(13):7267. https://doi.org/10.3390/ijms25137267
Chicago/Turabian StyleZisman, Devy, Hala Sabtan, Maya M. Rahat, Elina Simanovich, Amir Haddad, Tal Gazitt, Joy Feld, Gleb Slobodin, Adi Kibari, Muna Elias, and et al. 2024. "Tofacitinib Regulates Endostatin via Effects on CD147 and Cathepsin S" International Journal of Molecular Sciences 25, no. 13: 7267. https://doi.org/10.3390/ijms25137267