In the growing skeleton, angiogenesis is intimately coupled with osteogenesis. Chronic, high doses of glucocorticoids (GCs) are associated with decreased bone vasculature and induce osteoporosis and growth failure. The mechanism of GC‐suppression of angiogenesis and relationship to osteoporosis and growth retardation remains largely unknown. Type H vessels, which are regulated by preosteoclast (POC) platelet‐derived growth factor–BB (PDGF‐BB), are specifically coupled with bone formation and development. We determined the effect of GCs on POC synthesis of PDGF‐BB in relation to type H vessel formation, bone mass, and bone growth in the distal femur of 2‐week‐old young mice receiving prednisolone or vehicle for 2, 4, or 6 weeks. After 2 weeks of prednisolone, the number of POCs were unchanged while POC synthesis of PDGF‐BB was reduced. Longer treatment with prednisolone reduced POCs numbers and PDGF‐BB. These changes were associated with a reduction in type H vessels, bone formation rate, bone mass, and bone length at each time point. In vitro, excessive concentrations of prednisolone (10⁻⁶M) resulted in decreased PDGF‐BB concentration and POC numbers. Conditioned medium from POC cultures treated with control concentration of prednisolone (10⁻⁷M) or recombinant PDGF‐BB stimulated endothelial tube formation, whereas conditioned medium from control concentration of prednisolone‐treated POC cultures neutralized by PDGF‐BB antibody or excessive prednisolone inhibited endothelial tube formation. Administration of excessive prednisolone attenuated the P65 subunit of nuclear factor kappa B (NF‐κB) binding to the Pdgfb promoter, resulting in lower Pdgfb transcription. Co‐treatment with excessive prednisolone and the glucocorticoid receptor (GR) antagonist (RU486), GR siRNA, or TNFα rescued NF‐κB binding to the Pdgfb promoter and endothelial tube formation. These results indicate that PDGF‐BB synthesis in POCs is suppressed by GCs through transrepression of GR/NF‐κB, thus inhibiting type H vessel formation and associated osteoporosis and growth failure. © 2020 American Society for Bone and Mineral Research.

中文翻译：

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糖皮质激素通过反式抑制 NF-κB 介导的前破骨细胞 Pdgfb 转录在年轻小鼠中破坏骨骼血管生成。

在生长的骨骼中，血管生成与成骨密切相关。慢性、高剂量的糖皮质激素 (GCs) 与骨脉管系统减少有关，并诱发骨质疏松症和生长障碍。GC 抑制血管生成的机制以及与骨质疏松症和生长迟缓的关系仍然很大程度上未知。H 型血管受前破骨细胞 (POC) 血小板衍生生长因子-BB (PDGF-BB) 调节，与骨形成和发育特别相关。我们确定了 GCs 对 PDGF-BB 的 POC 合成与 H 型血管形成、骨量和接受泼尼松龙或载体 2、4 或 6 周的 2 周龄年轻小鼠股骨远端骨生长的影响周。泼尼松龙 2 周后，POC 的数量没有变化，而 PDGF-BB 的 POC 合成减少。泼尼松龙的长期治疗减少了 POC 数量和 PDGF-BB。这些变化与每个时间点 H 型血管、骨形成率、骨量和骨长度的减少有关。在体外，泼尼松龙浓度过高（10⁻⁶ M) 导致 PDGF-BB 浓度和 POC 数量降低。来自用对照浓度的泼尼松龙 (10 ^-7 M) 或重组 PDGF-BB 处理的 POC 培养物的条件培养基刺激内皮管形成，而来自对照浓度的泼尼松龙处理的 POC 培养物被 PDGF-BB 抗体或过量泼尼松龙中和的条件培养基抑制内皮管形成管形成。过量泼尼松龙的使用减弱了核因子 kappa B (NF-κB) 的 P65 亚基与 Pdgfb 启动子的结合，导致Pdgfb转录降低。过量泼尼松龙和糖皮质激素受体 (GR) 拮抗剂 (RU486)、GR siRNA 或 TNFα 共同治疗挽救了 NF-κB 与Pdgfb的结合启动子和内皮管形成。这些结果表明，GCs 通过 GR/NF-κB 的反式阻遏抑制 POCs 中的 PDGF-BB 合成，从而抑制 H 型血管形成和相关的骨质疏松症和生长障碍。© 2020 美国骨与矿物研究学会。