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Galunisertib downregulates mutant type I collagen expression and promotes MSCs osteogenesis in pediatric osteogenesis imperfecta.
Infante, Arantza; Alcorta-Sevillano, Natividad; Macías, Iratxe; Cabodevilla, Leire; Medhat, Dalia; Lafaver, Brittany; Crawford, Tara K; Phillips, Charlotte L; Bueno, Ana M; Sagastizabal, Belén; Arroyo, Maitane; Campino, Ainara; Gerovska, Daniela; Araúzo-Bravo, Marcos; Gener, Blanca; Rodríguez, Clara I.
Afiliação
  • Infante A; Stem Cells and Advanced Therapies Group, Biobizkaia Health Research Institute, Barakaldo, Spain.
  • Alcorta-Sevillano N; Stem Cells and Advanced Therapies Group, Biobizkaia Health Research Institute, Barakaldo, Spain; Department of Cell Biology and Histology, University of Basque Country UPV/EHU, Leioa, Spain.
  • Macías I; Stem Cells and Advanced Therapies Group, Biobizkaia Health Research Institute, Barakaldo, Spain.
  • Cabodevilla L; Stem Cells and Advanced Therapies Group, Biobizkaia Health Research Institute, Barakaldo, Spain.
  • Medhat D; Medical Biochemistry Department, National Research Centre, Dokki, Giza, Egypt.
  • Lafaver B; Department of Biochemistry, University of Missouri, Columbia, USA.
  • Crawford TK; Department of Biochemistry, University of Missouri, Columbia, USA.
  • Phillips CL; Department of Biochemistry, University of Missouri, Columbia, USA.
  • Bueno AM; Department of Orthopedic Surgery, Getafe University Hospital, Madrid, Spain.
  • Sagastizabal B; Department of Endocrinology, Getafe University Hospital, Madrid, Spain.
  • Arroyo M; Department of Traumatology, Basurto Hospital, Bilbao, Spain.
  • Campino A; Service of Pharmacy, Cruces University Hospital, Barakaldo, Spain.
  • Gerovska D; Computational Biology and Systems Biomedicine Research Group, Biogipuzkoa Health Research Institute, Donostia, Spain.
  • Araúzo-Bravo M; Computational Biology and Systems Biomedicine Research Group, Biogipuzkoa Health Research Institute, Donostia, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao 48009, Spain; Department of Cell Biology and Histology, Faculty of Medicine and Nursing, University of Basque Country (UPV/EHU), Spa
  • Gener B; Stem Cells and Advanced Therapies Group, Biobizkaia Health Research Institute, Barakaldo, Spain; Service of Genetics, Cruces University Hospital, Barakaldo, Spain.
  • Rodríguez CI; Stem Cells and Advanced Therapies Group, Biobizkaia Health Research Institute, Barakaldo, Spain. Electronic address: cirodriguez@osakidetza.eus.
Biomed Pharmacother ; 175: 116725, 2024 Jun.
Article em En | MEDLINE | ID: mdl-38744219
ABSTRACT
Qualitative alterations in type I collagen due to pathogenic variants in the COL1A1 or COL1A2 genes, result in moderate and severe Osteogenesis Imperfecta (OI), a rare disease characterized by bone fragility. The TGF-ß signaling pathway is overactive in OI patients and certain OI mouse models, and inhibition of TGF-ß through anti-TGF-ß monoclonal antibody therapy in phase I clinical trials in OI adults is rendering encouraging results. However, the impact of TGF-ß inhibition on osteogenic differentiation of mesenchymal stem cells from OI patients (OI-MSCs) is unknown. The following study demonstrates that pediatric skeletal OI-MSCs have imbalanced osteogenesis favoring the osteogenic commitment. Galunisertib, a small molecule inhibitor (SMI) that targets the TGF-ß receptor I (TßRI), favored the final osteogenic maturation of OI-MSCs. Mechanistically, galunisertib downregulated type I collagen expression in OI-MSCs, with greater impact on mutant type I collagen, and concomitantly, modulated the expression of unfolded protein response (UPR) and autophagy markers. In vivo, galunisertib improved trabecular bone parameters only in female oim/oim mice. These results further suggest that type I collagen is a tunable target within the bone ECM that deserves investigation and that the SMI, galunisertib, is a promising new candidate for the anti-TGF-ß targeting for the treatment of OI.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Osteogênese / Osteogênese Imperfeita / Pirazóis / Quinolinas / Regulação para Baixo / Colágeno Tipo I / Células-Tronco Mesenquimais Limite: Animals / Child / Child, preschool / Female / Humans / Male Idioma: En Revista: Biomed Pharmacother Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Osteogênese / Osteogênese Imperfeita / Pirazóis / Quinolinas / Regulação para Baixo / Colágeno Tipo I / Células-Tronco Mesenquimais Limite: Animals / Child / Child, preschool / Female / Humans / Male Idioma: En Revista: Biomed Pharmacother Ano de publicação: 2024 Tipo de documento: Article