Knockdown of POSTN Inhibits Osteogenic Differentiation of Mesenchymal Stem Cells From Patients With Steroid-Induced Osteonecrosis.
Knockdown of POSTN Inhibits Osteogenic Differentiation of Mesenchymal Stem Cells From Patients With Steroid-Induced Osteonecrosis.
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POSTN 的敲低会抑制类固醇引起的骨坏死患者的间充质干细胞的成骨分化。
DOI：
10.3389/fcell.2020.606289
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发表时间：
2020
影响因子：
5.5
通讯作者：
Xu W
中科院分区：
文献类型：
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作者：
Han L;Gong S;Wang R;Liu S;Wang B;Chen G;Gong T;Xu W
激素性股骨头坏死（Steroid-induced osteonecrosis of femoral head，SONFH）是长期和/或过量使用糖皮质激素（glucocorticoids，GC）引起的常见严重并发症。骨髓间充质干细胞（BMSCs）活性降低和分化异常被认为是该病发生和发展的主要原因之一。骨膜蛋白是一种基质细胞蛋白，在调节成骨细胞功能和骨形成中起重要作用。硬化素（Sclerostin，SOST）是一种分泌型Wnt信号拮抗剂，主要在骨细胞中表达，抑制骨形成。然而，POSTs和SOST在SONFH中的确切作用尚未报道。因此，我们检测了SONFH组患者BMSCs中POST 3和SOST的差异表达，并以创伤性ONFH（TONFH）和发育性髋关节发育不良（DDH）患者为对照组。此外，我们还采用慢病毒转染法，敲低SONFH患者BMSCs中POST 1的表达，研究POST 1的敲低对SOST表达和BMSCs成骨分化的影响。结果显示，SONFH组BMSCs内源性POST 3和SOST表达较对照组上调。对照组骨髓间充质干细胞成骨分化第0、3、7天POST表达逐渐上调，SOST表达逐渐下调。SONFH组骨髓间充质干细胞成骨分化过程中，POK表达逐渐下调，SOST表达逐渐上调。这可能是由于过多的GC导致BMSCs中SOST表达增加。而POST在骨髓间充质干细胞中的表达增加可能在拮抗SONFH患者骨髓间充质干细胞成骨分化过程中SOST的持续升高中发挥作用。在体外，POR 4基因敲低显著减弱了骨特异性基因表达、碱性磷酸酶活性和钙结节形成，从而抑制了SONFH患者BMSCs的成骨分化。此外，POST 3基因敲低上调SOST表达，增加GSK-3β活性，下调β-catenin表达。这些结果表明，POST 3在SOFH患者骨髓基质细胞的成骨分化和SOST表达中起重要作用，POST 3基因敲低通过上调SOST和部分失活Wnt/β-catenin信号通路抑制成骨分化。因此，靶向POSTs和SOST可能成为预防和治疗SONFH的有希望的治疗靶点。
Steroid-induced osteonecrosis of femoral head (SONFH) is a common and serious complication caused by long-term and/or excessive use of glucocorticoids (GCs). The decreased activity and abnormal differentiation of bone marrow mesenchymal stem cells (BMSCs) are considered to be one of the major reasons for the onset and progression of this disease. Periostin (POSTN) is a matricellular protein which plays an important role in regulating osteoblast function and bone formation. Sclerostin (SOST) is a secreted antagonist of Wnt signaling that is mainly expressed in osteocytes to inhibit bone formation. However, the exact role of POSTN and SOST in SONFH has not been reported yet. Therefore, we detected the differential expression of POSTN and SOST in BMSCs of SONFH Group patients, and Control Group was patients with traumatic ONFH (TONFH) and developmental dysplasia of the hip (DDH). Furthermore, we used lentiviral transfection to knockdown POSTN expression in BMSCs of patients with SONFH to study the effect of POSTN knockdown on the SOST expression and osteogenic differentiation of BMSCs. The results indicated that the endogenous expression of POSTN and SOST in BMSCs of SONFH Group was upregulated, compared with Control Group. POSTN was upregulated gradually while SOST was downregulated gradually at days 0, 3, and 7 of osteogenic differentiation of BMSCs in Control Group. Contrarily, POSTN was gradually downregulated while SOST was gradually upregulated during osteogenic differentiation of BMSCs in SONFH Group. This could be due to increased expression of SOST in BMSCs, which was caused by excessive GCs. In turn, the increased expression of POSTN in BMSCs may play a role in antagonizing the continuous rising of SOST during the osteogenic differentiation of BMSCs in patients with SONFH. POSTN knockdown significantly attenuated osteo-specific gene expression, alkaline phosphatase activity, and calcium nodule formation in vitro; thus inhibiting the osteogenic differentiation of BMSCs in patients with SONFH. Besides, POSTN knockdown upregulated SOST expression, increased GSK-3β activity, and downregulated β-catenin. These findings suggest that POSTN have an essential role in regulating the expression of SOST and osteogenic differentiation of BMSCs in patients with SONFH, and POSTN knockdown suppresses osteogenic differentiation by upregulating SOST and partially inactivating Wnt/β-catenin signaling pathway. Therefore, targeting POSTN and SOST may serve as a promising therapeutic target for the prevention and treatment of SONFH.