Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK.
Arthritis Res Ther. 2019 Aug 16;21(1):188. doi: 10.1186/s13075-019-1972-1.
Despite their efficacy in the treatment of chronic inflammation, the prolonged application of therapeutic glucocorticoids (GCs) is limited by significant systemic side effects including glucocorticoid-induced osteoporosis (GIOP). 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a bi-directional enzyme that primarily activates GCs in vivo, regulating tissue-specific exposure to active GC. We aimed to determine the contribution of 11β-HSD1 to GIOP.
Wild type (WT) and 11β-HSD1 knockout (KO) mice were treated with corticosterone (100 μg/ml, 0.66% ethanol) or vehicle (0.66% ethanol) in drinking water over 4 weeks (six animals per group). Bone parameters were assessed by micro-CT, sub-micron absorption tomography and serum markers of bone metabolism. Osteoblast and osteoclast gene expression was assessed by quantitative RT-PCR.
Wild type mice receiving corticosterone developed marked trabecular bone loss with reduced bone volume to tissue volume (BV/TV), trabecular thickness (Tb.Th) and trabecular number (Tb.N). Histomorphometric analysis revealed a dramatic reduction in osteoblast numbers. This was matched by a significant reduction in the serum marker of osteoblast bone formation P1NP and gene expression of the osteoblast markers Alp and Bglap. In contrast, 11β-HSD1 KO mice receiving corticosterone demonstrated almost complete protection from trabecular bone loss, with partial protection from the decrease in osteoblast numbers and markers of bone formation relative to WT counterparts receiving corticosterone.
This study demonstrates that 11β-HSD1 plays a critical role in GIOP, mediating GC suppression of anabolic bone formation and reduced bone volume secondary to a decrease in osteoblast numbers. This raises the intriguing possibility that therapeutic inhibitors of 11β-HSD1 may be effective in preventing GIOP in patients receiving therapeutic steroids.
尽管治疗慢性炎症的疗效显著，但长期应用治疗性糖皮质激素（GCs）受到显著的全身副作用的限制，包括糖皮质激素诱导的骨质疏松症（GIOP）。11β-羟类固醇脱氢酶 1 型（11β-HSD1）是一种双向酶，主要在体内激活 GCs，调节组织特异性暴露于活性 GC。我们旨在确定 11β-HSD1 对 GIOP 的贡献。
野生型（WT）和 11β-HSD1 敲除（KO）小鼠分别用皮质酮（100μg/ml，0.66%乙醇）或载体（0.66%乙醇）处理饮用水，持续 4 周（每组 6 只动物）。通过微 CT、亚微米吸收断层扫描和骨代谢血清标志物评估骨参数。通过定量 RT-PCR 评估成骨细胞和破骨细胞基因表达。
接受皮质酮的 WT 小鼠出现明显的小梁骨丢失，骨体积与组织体积比（BV/TV）、小梁厚度（Tb.Th）和小梁数量（Tb.N）降低。组织形态计量学分析显示成骨细胞数量明显减少。与之相对应的是，成骨细胞骨形成标志物 P1NP 的血清水平和 Alp 和 Bglap 等成骨细胞标志物的基因表达显著降低。相比之下，接受皮质酮的 11β-HSD1 KO 小鼠几乎完全免受小梁骨丢失的影响，与接受皮质酮的 WT 小鼠相比，成骨细胞数量和骨形成标志物的减少部分得到保护。
本研究表明，11β-HSD1 在 GIOP 中发挥关键作用，介导 GC 抑制合成代谢性骨形成和骨量减少，继发于成骨细胞数量减少。这提出了一个有趣的可能性，即治疗性抑制 11β-HSD1 的药物可能有效预防接受治疗性类固醇的患者发生 GIOP。
Zotero 插件
