Glucocorticoid-Induced Osteoporosis.
Glucocorticoid-Induced Osteoporosis.
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DOI：
10.1007/978-1-4939-2895-8_8
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发表时间：
2015
影响因子：
--
通讯作者：
Tuckermann J
中科院分区：
文献类型：
--
作者：
Frenkel B;White W;Tuckermann J
骨质疏松症是糖皮质激素（GC）治疗炎症和自身免疫性疾病的最具破坏性的副作用之一。来自人类和小鼠的证据表明，药理学GC给药数周内会产生有害的骨骼效应，与骨矿物质密度（BMD）降低相关或不相关。破骨细胞数量和骨吸收也迅速增加，与成骨细胞失活和骨形成减少一起，这些变化导致疾病初期BMD损失最快。然后骨吸收降低到亚生理水平，但骨形成的持续和严重抑制导致进一步的骨丢失和逐渐增加的骨折风险，高达比未治疗个体中观察到的高一个数量级。因此，骨形成成骨细胞被认为是GC诱导的骨质疏松症（GIO）的罪魁祸首。因此，我们主要集中在这方面的审查对成骨细胞的有害影响：抑制细胞的复制和功能和加速细胞凋亡。介导这些不良反应，GCs靶向控制成骨细胞生长、分化和存活的关键调节机制。具体而言，GC抑制生长因子途径，包括胰岛素生长因子、生长激素、肝细胞生长/分散因子和IL 6型细胞因子。它们还抑制下游激酶，包括PI 3-激酶和MAP激酶ERK，后者部分归因于MAP激酶磷酸酶1的直接转录刺激。然而，最重要的是，GC抑制Wnt信号通路，该通路在成骨细胞复制、功能和存活中起着关键作用。它们在转录上刺激Dkk和Sfrp家族的Wnt抑制剂的表达，并且它们诱导活性氧物质（ROS），这导致ROS活化的FoxO转录因子的β-连环蛋白的损失。鉴定解离的GC，这将抑制免疫系统而不引起骨质疏松症，被证明比最初认为的更具挑战性，GIO目前通过与双膦酸盐或PTH联合治疗来管理。然而，这些药物并不适合GIO。未来的治疗方法可能会针对GC靶点，如上述靶点，或新发现的靶点，包括Notch通路、AP-1/II 11轴和成骨细胞主调节因子RUNX 2。
Osteoporosis is among the most devastating side effects of glucocorticoid (GC) therapy for the management of inflammatory and auto-immune diseases. Evidence from both humans and mice indicate deleterious skeletal effects within weeks of pharmacological GC administration, both related and unrelated to a decrease in bone mineral density (BMD). Osteoclast numbers and bone resorption are also rapidly increased, and together with osteoblast inactivation and decreased bone formation, these changes lead the fastest loss in BMD during the initial disease phase. Bone resorption then decreases to sub-physiological levels, but persistent and severe inhibition of bone formation leads to further bone loss and progressively increased fracture risk, up to an order of magnitude higher than that observed in untreated individuals. Bone forming osteoblasts are thus considered the main culprits in GC-induced osteoporosis (GIO). Accordingly, we focus this review primarily on deleterious effects on osteoblasts: inhibition of cell replication and function and acceleration of apoptosis. Mediating these adverse effects, GCs target pivotal regulatory mechanisms that govern osteoblast growth, differentiation and survival. Specifically, GCs inhibit growth factor pathways, including Insulin Growth Factors, Growth Hormone, Hepatocyte Growth/Scatter Factor and IL6-type cytokines. They also inhibit downstream kinases, including PI3-kinase and the MAP kinase ERK, the latter attributable in part to direct transcriptional stimulation of MAP kinase phosphatase 1. Most importantly, however, GCs inhibit the Wnt signaling pathway, which plays a pivotal role in osteoblast replication, function and survival. They transcriptionally stimulate expression of Wnt inhibitors of both the Dkk and Sfrp families, and they induce reactive oxygen species (ROS), which result in loss of ß-catenin to ROS-activated FoxO transcription factors. Identification of dissociated GCs, which would suppress the immune system without causing osteoporosis, is proving more challenging than initially thought, and GIO is currently managed by co-treatment with bisphosphonates or PTH. These drugs, however, are not ideally suited for GIO. Future therapeutic approaches may aim at GC targets such as those mentioned above, or newly identified targets including the Notch pathway, the AP-1/Il11 axis and the osteoblast master regulator RUNX2.
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通过糖皮质激素受体和AP-1串扰来调节人骨髓基质细胞增殖和分化能力。
影响因子：
6.2
作者：
Carcamo-Orive, Ivan;Gaztelumendi, Ainhoa;Delgado, Jesus;Tejados, Naiara;Dorronsoro, Akaitz;Fernandez-Rueda, Jon;Pennington, Daniel J.;Trigueros, Cesar
通讯作者：
Trigueros, Cesar
DOI：
10.1006/bbrc.1997.7256
发表时间：
1997-09-08
影响因子：
3.1
作者：
Chaudhary, LR;Avioli, LV
通讯作者：
Avioli, LV
影响因子：
4.2
作者：
Chen, TL;Fry, D
通讯作者：
Fry, D
影响因子：
16
作者：
Biddie SC;John S;Sabo PJ;Thurman RE;Johnson TA;Schiltz RL;Miranda TB;Sung MH;Trump S;Lightman SL;Vinson C;Stamatoyannopoulos JA;Hager GL
通讯作者：
Hager GL
影响因子：
--
作者：
Bodine, PVN;Zhao, WG;Komm, BS
通讯作者：
Komm, BS