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Separating friend from foe: Inhibition of TGF-ß-induced detrimental SMAD1/5/9 phosphorylation while maintaining protective SMAD2/3 signaling in OA chondrocytes.
Thielen, Nathalie G M; van Caam, Arjan P M; V Beuningen, Henk M; Vitters, Elly L; van den Bosch, Martijn H J; Koenders, Marije I; van de Loo, Fons A J; Blaney Davidson, Esmeralda N; van der Kraan, Peter M.
Afiliação
  • Thielen NGM; Department of Experimental Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
  • van Caam APM; Department of Experimental Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
  • V Beuningen HM; Department of Experimental Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
  • Vitters EL; Department of Experimental Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
  • van den Bosch MHJ; Department of Experimental Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
  • Koenders MI; Department of Experimental Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
  • van de Loo FAJ; Department of Experimental Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
  • Blaney Davidson EN; Department of Experimental Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
  • van der Kraan PM; Department of Experimental Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands. Electronic address: Peter.vanderKraan@radboudumc.nl.
Osteoarthritis Cartilage ; 31(11): 1481-1490, 2023 11.
Article em En | MEDLINE | ID: mdl-37652257
ABSTRACT

OBJECTIVE:

Transforming growth factor-ß (TGF-ß) signaling via SMAD2/3 is crucial to control cartilage homeostasis. However, TGF-ß can also have detrimental effects by signaling via SMAD1/5/9 and thereby contribute to diseases like osteoarthritis (OA). In this study, we aimed to block TGF-ß-induced SMAD1/5/9 signaling in primary human OA chondrocytes, while maintaining functional SMAD2/3 signaling.

DESIGN:

Human OA chondrocytes were pre-incubated with different concentrations of ALK4/5/7 kinase inhibitor SB-505124 before stimulation with TGF-ß. Changes in SMAD C-terminal phosphorylation were analyzed using Western blot and response genes were measured with quantitative Polymerase Chain Reaction. To further explore the consequences of our ability to separate pathways, we investigated TGF-ß-induced chondrocyte hypertrophy.

RESULTS:

Pre-incubation with 0.5 µM SB-505124, maintained ±50% of C-terminal SMAD2/3 phosphorylation and induction of JUNB and SERPINE1, but blocked SMAD1/5/9-C phosphorylation and expression of ID1 and ID3. Furthermore, TGF-ß, in levels comparable to those in the synovial fluid of OA patients, resulted in regulation of hypertrophic and dedifferentiation markers in OA chondrocytes; i.e. an increase in COL10, RUNX2, COL1A1, and VEGF and a decrease in ACAN expression. Interestingly, in a subgroup of OA chondrocyte donors, blocking only SMAD1/5/9 caused stronger inhibition on TGF-ß-induced RUNX2 than blocking both SMAD pathways.

CONCLUSION:

Our findings indicate that using low dose of SB-505124 we maintained functional SMAD2/3 signaling that blocks RUNX2 expression in a subgroup of OA patients. We are the first to show that SMAD2/3 and SMAD1/5/9 pathways can be separately modulated using low and high doses of SB-505124 and thereby split TGF-ß's detrimental from protective function in chondrocytes.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Osteoartrite / Cartilagem Articular Limite: Humans Idioma: En Revista: Osteoarthritis Cartilage Assunto da revista: ORTOPEDIA / REUMATOLOGIA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Holanda

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Osteoartrite / Cartilagem Articular Limite: Humans Idioma: En Revista: Osteoarthritis Cartilage Assunto da revista: ORTOPEDIA / REUMATOLOGIA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Holanda