Chondrocytic and pharmacokinetic properties of Phlpp inhibitors.
| Autor: | Taylor EL; Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA., Weaver SR; Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA., Zars EL; Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA., Turner CA; University of Minnesota Rochester, Rochester, MN, USA., Buhrow SA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA., Reid JM; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA., Bradley EW; Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA.; Department of Orthopedic Surgery, University of Minnesota, Minneapolis, MN, USA., Westendorf JJ; Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA.; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA. |
|---|---|
| Jazyk: | angličtina |
| Zdroj: | Osteoarthritis and cartilage open [Osteoarthr Cartil Open] 2021 Jun 08; Vol. 3 (3), pp. 100190. Date of Electronic Publication: 2021 Jun 08 (Print Publication: 2021). |
| DOI: | 10.1016/j.ocarto.2021.100190 |
| Abstrakt: | Objective: The pleckstrin homology domain leucine-rich repeat protein phosphatases (Phlpp1/2) were recently identified as potential therapeutic targets for cartilage regeneration in osteoarthritic joints. Phlpp inhibitors NSC 117079 and NSC 45586 increase chondrocyte proliferation and matrix production, but the pharmacodynamics and pharmacokinetics of these compounds are not known. Design: Chondrocytic effects of Phlpp inhibitors, NSC 117079 and NSC 45586, were measured by western blotting of Phlpp substrates, glycosaminoglycan (GAG) assays, and transcriptomic assays. Liquid chromatography/mass spectroscopy assays were established to measure NSC 117079 and NSC 45586 in vitro and in vivo. The effects of NSC 117079 and NSC 45586 on articular cartilage structure in vivo after intra-articular injection were determined by histology. Results: The Phlpp inhibitors NSC 117079 and NSC 45586 were highly stable in vitro and stimulated GAG, Sox9, proteoglycan 4 and collagen 2 production in maturing but not more differentiated chondrocytes in vitro. Both molecules reduced Phlpp1/2 levels and suppressed matrix degradation to functionally extend their inhibitory effect on these phosphatases. In vivo, NSC 117079 was eliminated from the bloodstream within 4 h after intravenous injection, while NSC 45586 was eliminated in 8 h and had a higher volume distribution. Both molecules increased articular cartilage area on lateral and medial tibial plateaus and femoral condyles by 15% in C57Bl/6 mice between four and five weeks of age. Conclusion: These data advance our understanding of how Phlpp inhibitors promote and preserve cartilage formation and provide a basis for understanding their safety and activity in vivo. Competing Interests: None of the authors have any conflicts of interest. (© 2021 Mayo Clinic.) |
| Databáze: | MEDLINE |
| Externí odkaz: |
|