Concentrations of Adrenocorticotropic Hormone (ACTH1-24) Too Low to Effect Cortisol Enhance Osteogenesis In Vitro and In Vivo.

IF 3.1 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Irina L Tourkova, Reed A Rankin, Quitterie C Larrouture, Steve F Dobrowolski, Carlos M Isales, Harry C Blair
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Abstract

After finding that minimal amounts of adrenocorticotropic hormone (ACTH1-24) prevented osteonecrosis in rabbits, we studied bone formation at nanomolar ACTH1-24, in vivo in rabbits, and in vitro in human osteoblasts. ACTH1-24 in rabbits at 0.6 μg/kg/day had no measurable effect on cortisol. Groups of five rabbits given 0.6 μg/kg/day of ACTH1-24 enhanced trabecular bone in the rabbit femoral head relative to saline-treated controls (controls), increased bone volume/total volume (BV/TV) by micro-computed tomography, p<0.03. Xylenol orange and calcein labeling in vivo showed increased trabecular bone formation with 0.6 μg/kg/day of ACTH1-24, p = 0.0089 versus controls. In contrast, the cortex of the femoral shaft was unaffected, BV/TV p>0.95 ACTH1-24 versus controls. Bone marrow mRNA by PCR showed no change in osteoclast markers, and confirmed increased osteoblast markers, p<0.05. In vitro, ACTH1-24 elevated expression of Collagen 1, alkaline phosphatase (ALP), osteocalcin (BGLAP), and RunX2 in human osteoblasts differentiated on polyethylene terephthalate (PET) membranes. Optimal response was at 10-9 to 10-12 M. VEGF, VEGF receptors FLT-1 and FLK-1, and ACTH1-24 receptors MC2R were upregulated at 10-12 M ACTH1-24. Pathway analysis included increased BMP2, Smad1, Wnt-1, β-Catenin and TGF-β pathways. Because bone-forming osteoblasts are metabolically highly active, we studied mRNA expression of mitochondrial complex 1 (NDUFA5, NDUFS2, NDUFB1, NDUFB6) members with key roles in energy production. This increased at 10-12 M ACTH1-24. An ELISA for mitochondrial complex 1 activity showed maximum activity at 10-9 M and high activity at 10-12 M ACTH1-24. Thus, long-term very low dose ACTH1-24 increases bone formation in vivo and in vitro.

促肾上腺皮质激素(ACTH1-24)浓度过低而不影响皮质醇在体外和体内促进成骨。
在发现微量促肾上腺皮质激素(ACTH1-24)可以预防家兔骨坏死后,我们研究了纳摩尔ACTH1-24下家兔体内和体外人成骨细胞的骨形成。0.6 μg/kg/d剂量的ACTH1-24对皮质醇无显著影响。每组5只兔给予0.6 μg/kg/d的ACTH1-24,相对于盐水处理的对照组,兔股骨头小梁骨增强,微计算机断层扫描显示骨体积/总容积(BV/TV)增加,体内实验显示0.6 μg/kg/d的ACTH1-24增加了兔股骨头小梁骨形成,与对照组相比p = 0.0089。相比之下,股骨干皮质未受影响,BV/TV p>0.95 ACTH1-24与对照组相比。骨髓mRNA PCR显示破骨细胞标志物无变化,证实成骨细胞标志物升高,体外pIn、ACTH1-24、Collagen 1、碱性磷酸酶(ALP)、骨钙素(BGLAP)、RunX2在PET膜分化的人成骨细胞中表达升高。在10-9 ~ 10-12 M时,VEGF、VEGF受体FLT-1和FLK-1、ACTH1-24受体MC2R在10-12 M时表达上调。通路分析包括BMP2、Smad1、Wnt-1、β-Catenin和TGF-β通路升高。由于成骨成骨细胞代谢非常活跃,我们研究了线粒体复合体1 (NDUFA5、NDUFS2、NDUFB1、NDUFB6)成员的mRNA表达,这些成员在能量产生中起关键作用。在10-12 M ACTH1-24时增加。酶联免疫吸附法测定线粒体复合体1活性显示,ACTH1-24在10-9 M处活性最大,在10-12 M处活性较高。因此,长期极低剂量ACTH1-24在体内和体外均可促进骨形成。
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来源期刊
CiteScore
9.80
自引率
0.00%
发文量
98
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Endocrinology and Metabolism publishes original, mechanistic studies on the physiology of endocrine and metabolic systems. Physiological, cellular, and molecular studies in whole animals or humans will be considered. Specific themes include, but are not limited to, mechanisms of hormone and growth factor action; hormonal and nutritional regulation of metabolism, inflammation, microbiome and energy balance; integrative organ cross talk; paracrine and autocrine control of endocrine cells; function and activation of hormone receptors; endocrine or metabolic control of channels, transporters, and membrane function; temporal analysis of hormone secretion and metabolism; and mathematical/kinetic modeling of metabolism. Novel molecular, immunological, or biophysical studies of hormone action are also welcome.
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