Han Lizhi, Gong Song, Wang Ruoyu, Liu Shaokai, Wang Bo, Chen Guo, Gong Tianlun, Xu Weihua
Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Rehabilitation, Wuhan No.1 Hospital, Wuhan Hospital of Traditional Chinese and Western Medicine, Wuhan, China.
Front Cell Dev Biol. 2020 Dec 21;8:606289. doi: 10.3389/fcell.2020.606289. eCollection 2020.
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 ; 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.
糖皮质激素诱导的股骨头坏死（SONFH）是长期和/或过量使用糖皮质激素（GCs）引起的一种常见且严重的并发症。骨髓间充质干细胞（BMSCs）活性降低和异常分化被认为是该疾病发生和发展的主要原因之一。骨膜蛋白（POSTN）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。硬化蛋白（SOST）是Wnt信号的分泌拮抗剂，主要在骨细胞中表达以抑制骨形成。然而，POSTN和SOST在SONFH中的确切作用尚未见报道。因此，我们检测了SONFH组患者BMSCs中POSTN和SOST的差异表达，对照组为创伤性股骨头坏死（TONFH）和发育性髋关节发育不良（DDH）患者。此外，我们使用慢病毒转染敲低SONFH患者BMSCs中POSTN的表达，以研究POSTN敲低对BMSCs中SOST表达和成骨分化的影响。结果表明，与对照组相比，SONFH组BMSCs中POSTN和SOST的内源性表达上调。在对照组BMSCs成骨分化的第0、3和7天，POSTN逐渐上调而SOST逐渐下调。相反，在SONFH组BMSCs成骨分化过程中，POSTN逐渐下调而SOST逐渐上调。这可能是由于GCs过量导致BMSCs中SOST表达增加所致。反过来，SONFH患者BMSCs中POSTN表达增加可能在拮抗BMSCs成骨分化过程中SOST的持续升高方面发挥作用。敲低POSTN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，敲低POSTN上调了SOST表达，增加了GSK-3β活性，并下调了β-连环蛋白。这些发现表明，POSTN在调节SONFH患者BMSCs中SOST表达和成骨分化中起重要作用，敲低POSTN通过上调SOST和部分使Wnt/β-连环蛋白信号通路失活来抑制成骨分化。因此，靶向POSTN和SOST可能成为预防和治疗SONFH的有前景的治疗靶点。
