Lee Eun-Jin, Lialios Peter, Curtis Micaila, Williams James, Kim Yoontae, Salipante Paul, Hudson Steven, Esch Mandy B, Levi Moshe, Kitlinska Joanna, Alimperti Stella
Department of Biochemistry and Molecular and Cellular Biology, School of Medicine, Georgetown University, Washington, DC, 20057, USA.
Biological and Biomedical Engineering Center, School of Medicine, Georgetown University, Washington, DC, 20057, USA.
Adv Healthc Mater. 2025 Mar;14(7):e2404302. doi: 10.1002/adhm.202404302. Epub 2025 Jan 20.
Glucocorticoids (GCs) are standard-of-care treatments for inflammatory and immune disorders, and their long-term use increases the risk of osteoporosis. Although GCs decrease bone functionality, their role in bone microvasculature is incompletely understood. Herein, the study investigates the mechanisms of bone microvascular barrier function via osteoblast-endothelial interactions in response to GCs. The animal data shows that prednisolone (Psl) downregulated the osteoblast function and microvessel number and size. To investigate the role of GCs in bone endothelial barrier function further, a bicellular microfluidic in vitro system is developed and utilized, which consists of three-dimensional (3D) perfusable microvascular structures embedded in collagen I/osteoblast matrix. Interestingly, it is demonstrated that GCs significantly inhibit osteogenesis and microvascular barrier function by interfering with endothelial-osteoblast interactions. This effect is triggered by MAPK-induced phosphorylation of connexin43 (Cx43) at Ser282. Collectively, this study sheds light on microvascular function in bone disorders, as osteoporosis, and permits to capture dynamic changes in endothelial-bone interactions under GCs by dissecting the MAPK/Cx43 mechanism and proposing this as a potential target for bone diseases.
糖皮质激素（GCs）是治疗炎症和免疫疾病的标准疗法，长期使用会增加骨质疏松的风险。尽管GCs会降低骨功能，但其在骨微血管系统中的作用仍未完全明确。在此，本研究通过成骨细胞与内皮细胞的相互作用来探究糖皮质激素作用下骨微血管屏障功能的机制。动物实验数据表明，泼尼松龙（Psl）下调了成骨细胞功能以及微血管数量和大小。为进一步研究GCs在骨内皮屏障功能中的作用，我们开发并利用了一种双细胞微流控体外系统，该系统由嵌入I型胶原蛋白/成骨细胞基质中的三维（3D）可灌注微血管结构组成。有趣的是，研究表明GCs通过干扰内皮细胞与成骨细胞的相互作用，显著抑制骨生成和微血管屏障功能。这种效应是由丝裂原活化蛋白激酶（MAPK）诱导的连接蛋白43（Cx43）第282位丝氨酸磷酸化所触发的。总体而言，本研究揭示了骨质疏松等骨疾病中的微血管功能，并通过剖析MAPK/Cx43机制，捕捉了糖皮质激素作用下内皮细胞与骨相互作用的动态变化，为骨疾病提供了一个潜在靶点。
