Osteoclast-derived exosomal let-7a-5p targets Smad2 to promote the hypertrophic differentiation of chondrocytes
Osteoclast-derived exosomal let-7a-5p targets Smad2 to promote the hypertrophic differentiation of chondrocytes
复制标题
破骨细胞来源的外泌体let-7a-5p靶向Smad2促进软骨细胞的肥大分化
DOI：
10.1152/ajpcell.00039.2020
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发表时间：
2020-07-01
影响因子：
5.5
通讯作者：
Dong, Shiwu
中科院分区：
文献类型：
--
作者：
Dai, Jingjin;Dong, Rui;Dong, Shiwu
破骨细胞通过血管侵入软骨促进软骨内骨化过程，动态细胞间相互作用失调导致骨骼发育不良。虽然生长板软骨细胞对破骨细胞的调节已被详细报道，但破骨细胞对软骨细胞的影响仍有待确定。在这项研究中，ATDC 5细胞和骨髓间充质干细胞分化成软骨细胞，并与从骨髓巨噬细胞分化成破骨细胞前体和破骨细胞获得的条件培养基处理。外泌体在条件培养基中被抑制或直接从破骨细胞中分离，以进一步确定破骨细胞来源的外泌体是否在软骨细胞肥大中起重要作用。此外，检测到外泌体miRNA，并选择let-7a-5 p作为在破骨细胞来源的外泌体中具有显著增加的表达的miRNA。进行实验以验证潜在靶Smad 2并研究let-7a-5 p如何影响软骨细胞。结果提示，破骨细胞前体细胞和破骨细胞均能促进软骨细胞肥大，破骨细胞的促进作用比破骨细胞前体细胞更明显。破骨细胞来源的外泌体促进软骨细胞的肥大分化。此外，破骨细胞衍生的外泌体let-7a-5 p抑制Smad 2以降低转化生长因子β诱导的软骨细胞肥大抑制。我们的研究揭示了破骨细胞在调节软骨细胞中的作用，并为软骨内骨化的高度协调的细胞间过程提供了见解。
The invasion of osteoclasts into the cartilage via blood vessels advances the process of endochondral ossification, and dysregulation of dynamic intercellular interactions results in skeletal dysplasias. Although the regulation of osteoclasts by growth plate chondrocytes has been reported in detail, the effect of osteoclasts on chondrocytes remains to be determined. In this study, ATDC5 cells and bone marrow mesenchymal stem cells were differentiated into chondrocytes and treated with conditioned medium obtained from bone marrow macrophages differentiated to osteoclast precursors and osteoclasts. Exosomes were inhibited in conditioned medium or isolated directly from osteoclasts to further determine whether osteoclast-derived exosomes play an important role in chondrocyte hypertrophy. Additionally, exosomal miRNAs were detected, and let-7a-5p was selected as an miRNA with significantly increased expression in osteoclast-derived exosomes. Experiments were performed to verify the potential target Smad2 and investigate how let-7a-5p affected chondrocytes. The results suggest that both osteoclast precursors and osteoclasts promote chondrocyte hypertrophy and that the promotive effect of osteoclasts is more significant than that of osteoclast precursors. Osteoclast-derived exosomes promote the hypertrophic differentiation of chondrocytes. Moreover, osteoclast-derived exosomal let-7a-5p inhibits Smad2 to decrease the transforming growth factor-beta-induced inhibition of chondrocyte hypertrophy. Our research reveals the role of osteoclasts in the regulation of chondrocytes and provides insights into the highly coordinated intercellular process of endochondral ossification.