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A 3D System for Culturing Human Articular Chondrocytes in Synovial Fluid
Published on: January 31, 2012
Impaired Proteasomal Function in Human Osteoarthritic Chondrocytes Can Contribute to Decreased Levels of SOX9 and
Ramon L Serrano1, Liang-Yu Chen1, Martin K Lotz2
1VA San Diego Healthcare System, University of California San Diego, La Jolla, California.
Objective:
Osteoarthritis (OA) chondrocytes exhibit impairment of autophagy, one arm of the proteostasis network that coordinates proteome and organelle quality control and degradation. Deficient proteostasis impacts differentiation and viability, and inflammatory processes in aging and disease. The present study was undertaken to assess ubiquitin proteasome system proteasomal function in OA chondrocytes.
Methods:
We evaluated human knee cartilage by immunohistochemistry, and assessed proteasomal function, levels of proteasomal core subunits and chaperones, and autophagy in cultured chondrocytes. Assays included Western blotting, quantitative reverse transcription-polymerase chain reaction, proteasomal protease activity assessment, and cell immunofluorescence analysis.
Results:
Human knee OA cartilage exhibited polyubiquitin accumulation, with increased ubiquitin K48-linked polyubiquitinated proteins in situ, suggesting proteasomal impairment. Cultured OA chondrocytes demonstrated accumulation of K48 polyubiquitinated proteins, significantly reduced 20S proteasome core protease activity, and decreased levels of phosphorylated FOXO4 and proteasome 26S subunit, non-ATPase 11 (PSMD11), a FOXO4-inducible promoter of proteasomal activation. Levels of proteasome subunit β type 3 (PSMB3), PSMB5, PSMB6, and proteasome assembly chaperone 1 were not decreased in OA chondrocytes. In normal chondrocytes, PSMD11 small interfering RNA knockdown stimulated certain autophagy machinery elements, increased extracellular nitric oxide (NO) levels, and reduced chondrocytic master transcription factor SOX9 protein and messenger RNA (mRNA) and aggrecan (AGC1) mRNA. PSMD11 gain-of- function by transfection increased proteasomal function, increased levels of SOX9-induced AGC1 mRNA, stimulated elements of the autophagic machinery, and inhibited extracellular levels of interleukin-1-induced NO and matrix metalloproteinase 13 in OA chondrocytes.
Conclusion:
Deficient PSMD11, associated with reduced phosphorylated FOXO4, promotes impaired proteasomal function in OA chondrocytes, dysregulation of chondrocytic homeostasis, and decreased levels of SOX9 mRNA, SOX9 protein, and AGC1 mRNA. Chondrocyte proteasomal impairment may be a therapeutic target for OA.
Insights
Osteoarthritis chondrocytes show impaired proteasome function, linked to reduced PSMD11 levels. Restoring PSMD11 function may offer a therapeutic target for osteoarthritis.
Area of Science:
- Cell Biology
- Biochemistry
- Orthopedics
Background:
- Osteoarthritis (OA) is characterized by chondrocyte dysfunction, including impaired autophagy and proteostasis.
- Deficient proteostasis negatively impacts chondrocyte differentiation, viability, and contributes to inflammatory processes in aging and disease.
Purpose of the Study:
- To investigate the ubiquitin proteasome system (UPS) proteasomal function in OA chondrocytes.
- To assess the role of PSMD11 and its association with phosphorylated FOXO4 in OA chondrocyte homeostasis.
Main Methods:
- Human knee OA cartilage was evaluated using immunohistochemistry.
- Proteasomal function, subunit levels, and autophagy were assessed in cultured chondrocytes via Western blotting, qPCR, protease activity assays, and immunofluorescence.
Main Results:
- OA chondrocytes exhibited polyubiquitin accumulation and reduced proteasomal activity, specifically decreased 20S proteasome core protease activity.
- Levels of phosphorylated FOXO4 and PSMD11 were reduced in OA chondrocytes.
- PSMD11 gain-of-function in OA chondrocytes restored proteasomal function, increased SOX9 and aggrecan mRNA, and inhibited inflammatory mediators.
Conclusions:
- Impaired proteasomal function in OA chondrocytes, associated with deficient PSMD11 and reduced phosphorylated FOXO4, disrupts chondrocytic homeostasis.
- Targeting chondrocyte proteasomal impairment, particularly PSMD11, presents a potential therapeutic strategy for osteoarthritis.
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