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Chondrocytic and pharmacokinetic properties of Phlpp inhibitors
- Source :
- Osteoarthritis and Cartilage Open, Vol 3, Iss 3, Pp 100190-(2021)
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- 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.
- Subjects :
- PHLPP
SCOP
biology
Chemistry
Cartilage
Diseases of the musculoskeletal system
Articular cartilage
In vitro
Chondrocyte
nervous system diseases
Cell biology
Glycosaminoglycan
Blot
medicine.anatomical_structure
Proteoglycan 4
RC925-935
nervous system
In vivo
Osteoarthritis
medicine
biology.protein
Pharmacokinetics
biological phenomena, cell phenomena, and immunity
reproductive and urinary physiology
Subjects
Details
- ISSN :
- 26659131
- Volume :
- 3
- Database :
- OpenAIRE
- Journal :
- Osteoarthritis and Cartilage Open
- Accession number :
- edsair.doi.dedup.....0a68d39901116957a520382c903c4dcf