CurQ+, a Next-Generation Formulation of Curcumin, Ameliorates Growth Plate Chondrocyte Stress and Increases Limb Growth in a Mouse Model of Pseudoachondroplasia

Authors

Language

English

Publication Date

2-14-2023

Journal

International Journal of Molecular Sciences

DOI

10.3390/ijms24043845

PMID

36835255

PMCID

PMC9959842

PubMedCentral® Posted Date

2-14-2023

PubMedCentral® Full Text Version

Post-print

Abstract

Mutations in cartilage oligomeric matrix protein (COMP) causes protein misfolding and accumulation in chondrocytes that compromises skeletal growth and joint health in pseudoachondroplasia (PSACH), a severe dwarfing condition. Using the MT-COMP mice, a murine model of PSACH, we showed that pathological autophagy blockage was key to the intracellular accumulation of mutant-COMP. Autophagy is blocked by elevated mTORC1 signaling, preventing ER clearance and ensuring chondrocyte death. We demonstrated that resveratrol reduces the growth plate pathology by relieving the autophagy blockage allowing the ER clearance of mutant-COMP, which partially rescues limb length. To expand potential PSACH treatment options, CurQ+, a uniquely absorbable formulation of curcumin, was tested in MT-COMP mice at doses of 82.3 (1X) and 164.6 mg/kg (2X). CurQ+ treatment of MT-COMP mice from 1 to 4 weeks postnatally decreased mutant COMP intracellular retention, inflammation, restoring both autophagy and chondrocyte proliferation. CurQ+ reduction of cellular stress in growth plate chondrocytes dramatically reduced chondrocyte death, normalized femur length at 2X 164.6 mg/kg and recovered 60% of lost limb growth at 1X 82.3 mg/kg. These results indicate that CurQ+ is a potential therapy for COMPopathy-associated lost limb growth, joint degeneration, and other conditions involving persistent inflammation, oxidative stress, and a block of autophagy.

Keywords

Animals, Mice, Achondroplasia, Cartilage Oligomeric Matrix Protein, Chondrocytes, Curcumin, Disease Models, Animal, Extracellular Matrix Proteins, Growth Plate, Inflammation, Matrilin Proteins, Mutation, cartilage oligomeric matrix protein, COMP, autophagy, curcumin, dwarfism, chondrocyte, articular cartilage, joint degeneration

Published Open-Access

yes

Recommended Citation

, "CurQ+, a Next-Generation Formulation of Curcumin, Ameliorates Growth Plate Chondrocyte Stress and Increases Limb Growth in a Mouse Model of Pseudoachondroplasia" (2023). Faculty, Staff and Student Publications. 156.
https://digitalcommons.library.tmc.edu/uthdb_docs/156