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.

识别导致骨骼发育障碍的患者突变推动了我们对骨骼发育的理解。整合素粘附缺陷病是由 Kindlin-3（fermitin 家族成员 3）突变引起的，其失活导致出血性疾病和骨质减少。在这项研究中，我们揭示了 Kindlin-3 在骨髓间充质干细胞 (BMSCs) 向软骨形成谱系分化中的作用。Kindlin-3 表达随着软骨分化而增加，类似于 RUNX2。从 Kindlin-3 缺陷患者分离的 BMSC 在基础条件下表达软骨细胞标志物，包括 SOX9，随着软骨形成分化进一步增强。通过组成性激活的β3拯救整合素_激活整合素构建体增加了对多个细胞外基质的粘附，并将 SOX9 表达降低至基础水平。来自表达突变的 Kindlin-3 且整合素结合位点被消融的小鼠的生长板显示出软骨细胞成熟的改变，类似于人类 Kindlin-3 缺陷型骨髓间充质干细胞所见的改变。这些发现表明，Kindlin-3 表达反映了软骨形成过程中的 RUNX2。