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bioRxiv · 10.1101/578690

Kindlin-3 Mutation in Mesenchymal Stem Cells Results in Enhanced Chondrogenesis

Kerr, B.·Shi, L.·Jinnah, A.·Willey, J.·Lennon, D.·Caplan, A.·Byzova, T.
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Abstract

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 {beta}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.\n\nSUMMARYThis study by Kerr et al. describes a new role for Kindlin-3 in controlling early chondrocyte differentiation from mesenchymal stem cells and later hypertrophic differentiation of chondrocytes.

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Kerr, B., Shi, L., Jinnah, A., Willey, J., Lennon, D., Caplan, A., Byzova, T.. 2019-03-15. Kindlin-3 Mutation in Mesenchymal Stem Cells Results in Enhanced Chondrogenesis. https://doi.org/10.1101/578690

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