PDF(Pubmed)
Abstract：
Hindlimb suspension (HLS) mice exhibit osteoporosis of the hindlimb bones and may be an excellent model to test pharmacological interventions. We investigated the effects of inhibiting endoplasmic reticulum (ER) stress with 4-phenyl butyrate (4-PBA) on the morphology, physicochemical properties, and bone turnover markers of hindlimbs in HLS mice. We randomly divided 21 male C57BL/6J mice into three groups, ground-based controls, untreated HLS group and 4-PBA treated group (HLS+4PBA) (100mg/kg/day, intraperitoneal) for 21 days. We investigated histopathology, micro-CT imaging, Raman spectroscopic analysis, and gene expression. Untreated HLS mice exhibited reduced osteocyte density, multinucleated osteoclast-like cells, adipocyte infiltration, and reduced trabecular striations on micro-CT than the control group. Raman spectroscopy revealed higher levels of ER stress, hydroxyproline, non-collagenous proteins, phenylalanine, tyrosine, and CH2Wag as well as a reduction in proteoglycans and adenine. Furthermore, bone alkaline phosphatase and osteocalcin were downregulated, while Cathepsin K, TRAP, and sclerostin were upregulated. Treatment with 4-PBA partially restored normal bone histology, increased collagen crosslinking, and mineralization, promoted anti-inflammatory markers, and downregulated bone resorption markers. Our findings suggest that mitigating ER stress with 4-PBA could be a therapeutic intervention to offset osteoporosis in conditions mimicking hindlimb suspension.
摘要：
后肢悬吊（HLS）小鼠表现出后肢骨骼的骨质疏松症，可能是测试药理学干预措施的出色模型。我们研究了4-苯基丁酸（4-PBA）抑制内质网（ER）应激对形态学的影响，物理化学性质，和HLS小鼠后肢的骨转换标记。我们将21只雄性C57BL/6J小鼠随机分为三组，地面控制，未经治疗的HLS组和4-PBA治疗组（HLS+4PBA）（100mg/kg/天，腹膜内）21天。我们调查了组织病理学,显微CT成像,拉曼光谱分析,和基因表达。未经治疗的HLS小鼠表现出降低的骨细胞密度，多核破骨细胞样细胞,脂肪细胞浸润，与对照组相比，显微CT上的小梁条纹减少。拉曼光谱揭示了更高水平的内质网应激，羟脯氨酸,非胶原蛋白，苯丙氨酸,酪氨酸,和CH2Wag以及蛋白聚糖和腺嘌呤的减少。此外，骨碱性磷酸酶和骨钙蛋白下调，而组织蛋白酶K,陷阱,硬化蛋白上调。4-PBA治疗部分恢复正常骨组织，增加胶原蛋白交联，和矿化，促进抗炎标志物，和下调的骨吸收标志物。我们的发现表明，在模仿后肢悬吊的情况下，用4-PBA减轻内质网应激可能是抵消骨质疏松症的治疗干预措施。
