背景:我们最近的研究表明,粘着斑蛋白Kindlin-2在间充质干细胞中发挥着至关重要的功能,成熟的成骨细胞和骨细胞控制小鼠早期骨骼发育和骨稳态。然而,Kindlin-2是否在骨祖细胞中发挥作用尚不清楚.
方法:在表达Osterix(Osx)的细胞中缺乏Kindlin-2表达的小鼠(即,骨祖细胞)产生。微计算机断层扫描(μCT)分析,组织学,进行骨组织形态计量学和免疫组织化学,以确定Kindlin-2缺失对骨骼发育、骨量累积和体内平衡的影响.分离来自突变小鼠(Kindlin-2fl/fl;OsxCre)和对照同窝的骨髓基质细胞(BMSC),并确定其成骨细胞分化能力。
结果:Kindlin-2在软骨内骨化过程中骨祖细胞中高表达。骨祖细胞中Kindlin-2表达的缺失损害了膜内和软骨内骨化。突变小鼠表现出多种严重的骨骼异常,包括未矿化的fontanel,肢体缩短和生长迟缓。骨祖细胞中Kindlin-2的缺失会损害生长板的发育,并大大延迟了长骨中次要骨化中心的形成。此外,成年突变小鼠表现出严重的低周转性骨质减少,骨形成急剧下降,超过了骨吸收。从突变小鼠分离的原代BMSCs表现出降低的成骨细胞分化能力。
结论:我们的研究表明,Kinlind-2在骨祖细胞中的表达在调节小鼠骨骼生成、骨量积累和体内平衡方面具有重要作用。
■这项研究揭示了Kindlin-2通过其在骨祖细胞中的表达来控制软骨形成和骨量。我们可以为骨骼疾病的治疗定义一个新的治疗靶点,如软骨发育不良和骨质疏松症。
BACKGROUND: Our recent studies demonstrate that the focal adhesion protein Kindlin-2 exerts crucial functions in the mesenchymal stem cells, mature osteoblasts and osteocytes in control of early skeletal development and bone homeostasis in mice. However, whether Kindlin-2 plays a role in osteoprogenitors remains unclear.
METHODS: Mice lacking Kindlin-2 expression in osterix (Osx)-expressing cells (i.e., osteoprogenitors) were generated. Micro-computerized tomography (μCT) analyses, histology, bone histomorphometry and immunohistochemistry were performed to determine the effects of Kindlin-2 deletion on skeletal development and bone mass accrual and homeostasis. Bone marrow stromal cells (BMSCs) from mutant mice (Kindlin-2 fl/fl ; Osx Cre ) and control littermates were isolated and determined for their osteoblastic differentiation capacity.
RESULTS: Kindlin-2 was highly expressed in osteoprogenitors during endochondral ossification. Deleting Kindlin-2 expression in osteoprogenitors impaired both intramembranous and endochondral ossifications. Mutant mice displayed multiple severe skeletal abnormalities, including unmineralized fontanel, limb shortening and growth retardation. Deletion of Kindlin-2 in osteoprogenitors impaired the growth plate development and largely delayed formation of the secondary ossification center in the long bones. Furthermore, adult mutant mice displayed a severe low-turnover osteopenia with a dramatic decrease in bone formation which exceeded that in bone resorption. Primary BMSCs isolated from mutant mice exhibited decreased osteoblastic differentiation capacity.
CONCLUSIONS: Our study demonstrates an essential role of Kinlind-2 expression in osteoprogenitors in regulating skeletogenesis and bone mass accrual and homeostasis in mice.
UNASSIGNED: This study reveals that Kindlin-2 through its expression in
osteoprogenitor cells controls chondrogenesis and bone mass. We may define a novel therapeutic target for treatment of skeletal diseases, such as chondrodysplasia and osteoporosis.