Kindlin-3 mutation in mesenchymal stem cells results in enhanced chondrogenesis.
Kindlin-3 mutation in mesenchymal stem cells results in enhanced chondrogenesis.
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DOI：
10.1016/j.yexcr.2020.112456
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发表时间：
2021-02-15
影响因子：
3.7
通讯作者：
Byzova TV
中科院分区：
文献类型：
--
作者：
Kerr BA;Shi L;Jinnah AH;Harris KS;Willey JS;Lennon DP;Caplan AI;Byzova TV
识别驱动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（费米子蛋白家族成员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，我们发现Kindlin-3在骨髓间充质干细胞（BMSCs）向软骨细胞系分化中的作用。Kindlin-3表达随着软骨分化而增加，与RUNX 2相似。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SOX 9，其进一步增强成软骨分化。通过组成性活化的β3整联蛋白构建体拯救整联蛋白活化增加了与多种细胞外基质的粘附并将SOX 9表达降低至基础水平。来自表达突变的Kindlin-3且整联蛋白结合位点被切除的小鼠的生长板显示出软骨细胞成熟的改变，其类似于在人Kindlin-3缺陷型BMSC中观察到的改变。这些发现表明Kindlin-3表达反映了软骨形成过程中的RUNX 2。
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.
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DOI：
10.1083/jcb.126.6.1611
发表时间：
1994-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Amizuka N;Warshawsky H;Henderson JE;Goltzman D;Karaplis AC
通讯作者：
Karaplis AC
DOI：
10.1002/jbmr.2287
发表时间：
2014-12
期刊：
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
影响因子：
--
作者：
Chen H;Ghori-Javed FY;Rashid H;Adhami MD;Serra R;Gutierrez SE;Javed A
通讯作者：
Javed A
影响因子：
3.7
作者：
Olivares-Navarrete R;Lee EM;Smith K;Hyzy SL;Doroudi M;Williams JK;Gall K;Boyan BD;Schwartz Z
通讯作者：
Schwartz Z
影响因子：
8
作者：
McCabe, N. P.;De, S.;Byzova, T. V.
通讯作者：
Byzova, T. V.
影响因子：
56.9
作者：
Fang, F;Orend, G;Ruoslahti, E
通讯作者：
Ruoslahti, E