PT  - JOURNAL ARTICLE
AU  - Bethany A. Kerr
AU  - Lihong Shi
AU  - Alexander H. Jinnah
AU  - Jeffrey S. Willey
AU  - Donald P. Lennon
AU  - Arnold I. Caplan
AU  - Tatiana V. Byzova
TI  - Kindlin-3 Mutation in Mesenchymal Stem Cells Results in Enhanced Chondrogenesis
AID  - 10.1101/578690
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 578690
4099  - http://biorxiv.org/content/early/2019/03/15/578690.short
4100  - http://biorxiv.org/content/early/2019/03/15/578690.full
AB  - 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 β3 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.SUMMARY This 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.3Dthree dimensionalBMSCBone marrow-derived mesenchymal stem cellBSABovine serum albuminDMEM-LGDulbecco’s Modified Eagle’s Medium-Low GlucoseIADDintegrin adhesions deficiency diseaseK3KIKindlin-3 knock-inLADleukocyte adhesion deficiencyMSCmesenchymal stem cellTGFtransforming growth factorTRAPtartrate-resistant acid phosphatase