A crucial role of caspase-3 in osteogenic differentiation of bone marrow stromal stem cells
A crucial role of caspase-3 in osteogenic differentiation of bone marrow stromal stem cells
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DOI：
10.1172/jci200420427
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发表时间：
2004-12-01
影响因子：
15.9
通讯作者：
Shi, ST
中科院分区：
文献类型：
--
作者：
Miura, M;Chen, XD;Shi, ST
Caspase-3是细胞凋亡和细胞存活的关键酶。在这里，我们报告了由于骨髓基质干细胞（BMSSCs）的成骨分化减弱而导致的caspase-3缺陷（Casp 3（-/-）和Casp 3（+/-））小鼠的骨化延迟和骨密度降低。BMSSCs分化受损的机制至少部分是由于过度激活的TGF-β/Smad 2信号通路和上调的p53和p21表达沿着下调的Cdk 2和Cdc 2表达，并最终增加了复制性衰老。此外，过度激活的TGF-β/Smad 2信号可能导致前成骨细胞中Runx 2/Cbfa 1表达受损。此外，我们证明，caspase-3抑制剂，一种潜在的药物，用于临床治疗人类疾病，造成加速骨质流失的卵巢切除小鼠，这也与过度激活的TGF-β/Smad 2信号在BMSSCs。本研究表明caspase-3通过影响TGF-β/Smad 2通路和细胞周期进程对BMSSCs的分化起着至关重要的作用。
Caspase-3 is a critical enzyme for apoptosis and cell survival. Here we report delayed ossification and decreased bone mineral density in caspase-3-deficient (Casp3(-/-) and Casp3(+/-)) mice due to an attenuated osteogenic differentiation of bone marrow stromal stem cells (BMSSCs). The mechanism involved in the impaired differentiation of BMSSCs is due, at least partially, to the overactivated TGF-beta/Smad2 signaling pathway and the upregulated expressions of p53 and p21 along with the downregulated expressions of Cdk2 and Cdc2, and ultimately increased replicative senescence. In addition, the overactivated TGF-beta/Smad2 signaling may result in the compromised Runx2/Cbfa1 expression in preosteoblasts. Furthermore, we demonstrate that caspase-3 inhibitor, a potential agent for clinical treatment of human diseases, caused accelerated bone loss in ovariectomized mice, which is also associated with the overactivated TGF-beta/Smad2 signaling in BMSSCs. This study demonstrates that caspase-3 is crucial for the differentiation of BMSSCs by influencing TGF-beta/Smad2 pathway and cell cycle progression.