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Generation of the Chondroprotective Proteomes by Activating PI3K and TNFα Signaling
Xun Sun1,2, Ke-Xin Li1,2, Marxa L Figueiredo3
1Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin 150081, China.
Purpose:
To develop a novel treatment option for Chondrosarcoma (CS) and inflammatory arthritis, we evaluated a counterintuitive approach of activating tumorigenic and inflammatory signaling for generating joint-protective proteomes.
Methods:
We employed mesenchymal stem cells and chondrocytes to generate chondroprotective proteomes by activating PI3K signaling and the administration of TNFα. The efficacy of the proteomes was examined using human and mouse cell lines as well as a mouse model of CS. The regulatory mechanism was analyzed using mass spectrometry-based whole-genome proteomics.
Results:
While tumor progression and inflammatory responses were promoted by activating PI3K signaling and the administration of TNFα to CS cells and chondrocytes, those cells paradoxically generated a chondroprotective conditioned medium (CM). The application of CM downregulated tumorigenic genes in CS cells and TNFα and MMP13 in chondrocytes. Mechanistically, Hsp90ab1 was enriched in the chondroprotective CM, and it immunoprecipitated GAPDH. Extracellular GAPDH interacted with L1CAM and inhibited tumorigenic behaviors, whereas intracellular GAPDH downregulated p38 and exerted anti-inflammatory effects.
Conclusions:
We demonstrated that the unconventional approach of activating oncogenic and inflammatory signaling can generate chondroprotective proteomes. The role of Hsp90ab1 and GAPDH differed in their locations and they acted as the uncommon protectors of the joint tissue from tumor and inflammatory responses.
Insights
Activating tumor and inflammatory pathways paradoxically created joint-protective proteomes. Heat shock protein 90 beta 1 (Hsp90ab1) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) protected joint tissue from chondrosarcoma and inflammation.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Chondrosarcoma (CS) and inflammatory arthritis pose significant challenges.
- Existing treatments often have limitations.
- Novel therapeutic strategies are needed to protect joint tissue.
Purpose of the Study:
- To explore a novel approach for treating CS and inflammatory arthritis.
- To investigate the generation of joint-protective proteomes by activating tumorigenic and inflammatory signaling pathways.
Main Methods:
- Mesenchymal stem cells and chondrocytes were used to generate chondroprotective proteomes.
- PI3K signaling activation and TNFα administration were employed.
- Efficacy was tested in human and mouse cell lines and a CS mouse model.
- Whole-genome proteomics analyzed regulatory mechanisms.
Main Results:
- Activating PI3K signaling and TNFα promoted tumor progression and inflammation but generated chondroprotective conditioned medium (CM).
- CM downregulated tumorigenic genes in CS cells and inflammatory markers (TNFα, MMP13) in chondrocytes.
- Hsp90ab1 and GAPDH were identified as key proteins in the CM, with distinct intracellular and extracellular roles.
Conclusions:
- An unconventional strategy of activating oncogenic and inflammatory signaling can yield chondroprotective proteomes.
- Hsp90ab1 and GAPDH, through their location-specific functions, protect joint tissue from chondrosarcoma and inflammation.
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