Identification of Transcription Factors Responsible for a Transforming Growth Factor-ß-Driven Hypertrophy-like Phenotype in Human Osteoarthritic Chondrocytes.
Cells
; 11(7)2022 04 05.
Article
en En
| MEDLINE
| ID: mdl-35406794
During osteoarthritis (OA), hypertrophy-like chondrocytes contribute to the disease process. TGF-ß's signaling pathways can contribute to a hypertrophy(-like) phenotype in chondrocytes, especially at high doses of TGF-ß. In this study, we examine which transcription factors (TFs) are activated and involved in TGF-ß-dependent induction of a hypertrophy-like phenotype in human OA chondrocytes. We found that TGF-ß, at levels found in synovial fluid in OA patients, induces hypertrophic differentiation, as characterized by increased expression of RUNX2, COL10A1, COL1A1, VEGFA and IHH. Using luciferase-based TF activity assays, we observed that the expression of these hypertrophy genes positively correlated to SMAD3:4, STAT3 and AP1 activity. Blocking these TFs using specific inhibitors for ALK-5-induced SMAD signaling (5 µM SB-505124), JAK-STAT signaling (1 µM Tofacitinib) and JNK signaling (10 µM SP-600125) led to the striking observation that only SB-505124 repressed the expression of hypertrophy factors in TGF-ß-stimulated chondrocytes. Therefore, we conclude that ALK5 kinase activity is essential for TGF-ß-induced expression of crucial hypertrophy factors in chondrocytes.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Osteoartritis
/
Condrocitos
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Cells
Año:
2022
Tipo del documento:
Article
País de afiliación:
Países Bajos
Pais de publicación:
Suiza