Department of Orthopaedics, The Second Affiliated Hospital of Chongqing Medical University, 76 Linjiang Road, Yuzhong District, Chongqing 400010, PR China; Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, No. 1 Yixueyuan Road, Yuzhong District, Chongqing 400010, PR China.
Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, No. 1 Yixueyuan Road, Yuzhong District, Chongqing 400010, PR China; Department of Pharmacology, School of Pharmacy, Chongqing Medical University, No. 1 Yixueyuan Road, Yuzhong District, Chongqing 400010, PR China.
J Steroid Biochem Mol Biol. 2019 Jul;191:105363. doi: 10.1016/j.jsbmb.2019.04.012. Epub 2019 Apr 21.
Glucocorticoid-Induced Osteoporosis (GIOP) is a prevalent clinical complication caused by large dose administration of glucocorticoids, such as Dexamethasone (Dex) and Prednisone. GIOP may lead to fractures and even Osteonecrosis of the Femoral Head (ONFH). It has been reported that glucocorticoids inhibit osteogenesis via the suppression of osteogenic differentiation in Mesenchymal Stem Cells (MSCs), but the precise mechanism underlying this suppression awaits further investigation. Meanwhile, novel and efficacious therapies are recommended to cope with GIOP. In this study, we demonstrated that Dex had the inhibitory effect on Bone Morphogenetic Protein 9 (BMP9)-induced ALP activities and matrix mineralization in Mouse Embryonic Fibroblasts (MEFs). In addition, the study confirmed that Dex decreased the expression of osteogenic markers such as Runx2 and OPN. However, the inhibitory effect of Dex on these osteogenic markers can be reversed when combined with insulin-like growth factor 1 (IGF-1). Regarding the inhibitory mechanism, we found that the level of AKT and p-AKT can be decreased by Dex and that Ly294002, the PI3K inhibitor, can block the reversal effect of IGF-1. Moreover, the knockdown or inhibition of COX-2 produced similar results to those of Ly294002. Our findings indicated that IGF-1 may reverse the osteogenic inhibitory effect of Dex via PI3K/AKT pathway, which may be associated with the up-regulation of COX-2. This study may provide new clinical management strategy for GIOP cases.
糖皮质激素诱导性骨质疏松症（GIOP）是一种由大剂量糖皮质激素（如地塞米松（Dex）和泼尼松）引起的常见临床并发症。GIOP 可导致骨折，甚至股骨头坏死（ONFH）。据报道，糖皮质激素通过抑制间充质干细胞（MSCs）中的成骨分化来抑制成骨作用，但这种抑制的确切机制仍有待进一步研究。同时，建议采用新的有效疗法来应对 GIOP。在这项研究中，我们证明了 Dex 对骨形态发生蛋白 9（BMP9）诱导的 MEFs 碱性磷酸酶（ALP）活性和基质矿化有抑制作用。此外，研究证实 Dex 降低了成骨标志物如 Runx2 和 OPN 的表达。然而，当与胰岛素样生长因子 1（IGF-1）联合使用时，Dex 对这些成骨标志物的抑制作用可以逆转。关于抑制机制，我们发现 Dex 可以降低 AKT 和 p-AKT 的水平，而 PI3K 抑制剂 Ly294002 可以阻断 IGF-1 的逆转作用。此外，COX-2 的敲低或抑制也产生了类似于 Ly294002 的结果。我们的研究结果表明，IGF-1 可能通过 PI3K/AKT 通路逆转 Dex 的成骨抑制作用，这可能与 COX-2 的上调有关。这项研究可为 GIOP 病例提供新的临床管理策略。
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