Kindlin-3 mutation in mesenchymal stem cells results in enhanced chondrogenesis.

Autor: Kerr BA; Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA; Department of Orthopaedic Surgery, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA. Electronic address: bkerr@wakehealth.edu., Shi L; Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA., Jinnah AH; Department of Orthopaedic Surgery, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA., Harris KS; Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA., Willey JS; Department of Orthopaedic Surgery, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA; Department of Radiation Biology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA., Lennon DP; Skeletal Research Center, Department of Biology, Case Western Reserve University, Cleveland, OH, 44106, USA., Caplan AI; Skeletal Research Center, Department of Biology, Case Western Reserve University, Cleveland, OH, 44106, USA., Byzova TV; Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
Jazyk: angličtina
Zdroj: Experimental cell research [Exp Cell Res] 2021 Feb 15; Vol. 399 (2), pp. 112456. Date of Electronic Publication: 2021 Jan 05.
DOI: 10.1016/j.yexcr.2020.112456
Abstrakt: Identifying patient mutations driving skeletal development disorders has driven our understanding of bone development. Integrin adhesion deficiency disease is caused by a Kindlin-3 (fermitin family member 3) mutation, and its inactivation results in bleeding disorders and osteopenia. In this study, we uncover a role for Kindlin-3 in the differentiation of bone marrow mesenchymal stem cells (BMSCs) down the chondrogenic lineage. Kindlin-3 expression increased with chondrogenic differentiation, similar to RUNX2. BMSCs isolated from a Kindlin-3 deficient patient expressed chondrocyte markers, including SOX9, under basal conditions, which were further enhanced with chondrogenic differentiation. Rescue of integrin activation by a constitutively activated β 3 integrin construct increased adhesion to multiple extracellular matrices and reduced SOX9 expression to basal levels. Growth plates from mice expressing a mutated Kindlin-3 with the integrin binding site ablated demonstrated alterations in chondrocyte maturation similar to that seen with the human Kindlin-3 deficient BMSCs. These findings suggest that Kindlin-3 expression mirrors RUNX2 during chondrogenesis.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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