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Updated: Nov 22, 2025
Chondrogenic Differentiation Induction of Adipose-derived Stem Cells by Centrifugal Gravity
Published on: February 24, 2017
Kindlin-3 mutation in mesenchymal stem cells results in enhanced chondrogenesis
Bethany A Kerr1, Lihong Shi2, Alexander H Jinnah3
1Department 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.
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 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.
Insights
Kindlin-3 plays a crucial role in bone development by regulating chondrogenic differentiation of mesenchymal stem cells. Its deficiency leads to altered chondrocyte maturation, impacting skeletal development.
Area of Science:
- Biochemistry
- Cell Biology
- Genetics
Background:
- Integrin adhesion deficiency disease, caused by Kindlin-3 mutations, leads to bleeding disorders and osteopenia.
- Understanding the molecular mechanisms of skeletal development is crucial for treating bone disorders.
Purpose of the Study:
- To investigate the role of Kindlin-3 in the chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs).
- To elucidate the impact of Kindlin-3 deficiency on skeletal development and chondrocyte maturation.
Main Methods:
- Assessed Kindlin-3 expression during chondrogenic differentiation of BMSCs.
- Analyzed chondrocyte marker expression (SOX9) in BMSCs from Kindlin-3 deficient patients.
- Utilized a constitutively activated β3 integrin construct to rescue integrin activation.
- Examined chondrocyte maturation in growth plates of mice with mutated Kindlin-3.
Main Results:
- Kindlin-3 expression increased with chondrogenic differentiation, mirroring RUNX2.
- Kindlin-3 deficient BMSCs showed elevated SOX9 expression under basal and differentiated conditions.
- Restoring integrin activation reduced SOX9 expression to basal levels.
- Kindlin-3 mutations in mice led to altered chondrocyte maturation.
Conclusions:
- Kindlin-3 is essential for regulating chondrogenic differentiation and BMSC fate.
- Kindlin-3 deficiency contributes to skeletal development disorders through impaired chondrocyte maturation.
- Kindlin-3's role in chondrogenesis is linked to integrin activation and extracellular matrix interactions.
