Orchiectomy upregulates free soluble RANKL in bone marrow of aged rats
Orchiectomy upregulates free soluble RANKL in bone marrow of aged rats
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DOI：
10.1016/j.bone.2009.05.024
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发表时间：
2009-10-01
期刊：
影响因子：
4.1
通讯作者：
Erben, Reinhold G.
中科院分区：
文献类型：
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作者：
Proell, Verena;Xu, Huiqing;Erben, Reinhold G.
骨保护素（OPG）/NF-κ B配体受体激活因子（RANKL）轴被认为参与性类固醇缺乏后骨转换的上调。在这里，我们研究了睾丸切除术（ORX）对老年大鼠骨转换和游离可溶性RANKL（sRANKL）的影响。游离的、具有生物活性的sRANKL是成熟破骨细胞存活和活性的关键决定因素和关键介质。对33只9月龄雄性Fischer-344大鼠进行ORX或假手术（SHAM）。在体内荧光染料标记后，将媒介物（蓖麻油/苯甲酸苄酯）处理的SHAM和媒介物-或十一烷酸睾酮（T，6mg/kg s.c.每周一次）处理的ORX大鼠（每只n = 8 - 9）在手术后2个月处死。通过外周定量计算机断层扫描测量，与SHAM对照组相比，溶剂处理的ORX大鼠表现出较低的精囊重量、近端胫骨骨小梁骨矿物质密度损失和胫骨干皮质厚度减少。溶剂处理的ORX大鼠的骨丢失与骨转换增强相关，如胫骨松质骨形成率、破骨细胞数量、尿钙和脱氧吡啶啉排泄以及血清骨钙素增加所证明。ORX大鼠的T治疗使精囊重量恢复到SHAM对照水平，并通过抑制骨转换完全防止ORX后骨丢失。从股骨近端采集的骨髓上清液中的游离sRANKL浓度在溶剂处理的ORX大鼠中约为SHAM大鼠的3倍，在T处理的ORX大鼠中恢复至SHAM对照水平。骨髓中基质金属蛋白酶-14（MMP-14）的mRNA丰度在溶剂处理的ORX大鼠中相对于SHAM大鼠高4倍。T处理的ORX大鼠抑制MMP-14 mRNA表达至SHAM对照水平。我们得出结论，睾丸切除术增加了老年大鼠骨髓中游离sRANKL的浓度。此外，MMP-14增加膜结合RANKL的脱落可能是导致雄激素戒断后骨髓环境中游离sRANKL浓度增加的关键机制。(c)2009 Elsevier Inc. All rights reserved.
The osteoprotegerin (OPG)/receptor activator of NF-kappa B ligand (RANKL) axis is thought to be involved in the Upregulation of bone turnover following sex steroid deficiency. Here, we investigated the effects of orchiectomy (ORX) on bone turnover and free Soluble RANKL (sRANKL) in aged rats. Free, bioactive sRANKL is a critical determinant and key mediator for Survival and activity of mature osteoclasts. Thirty-three 9-month-old male Fischer-344 rats were either ORX or sham-operated (SHAM). Following in vivo fluorochrome labeling, vehicle (ricinus oil/benzyl benzoate)-treated SHAM and vehicle- or testosterone unclecanoate (T, 6 mg/kg s.c. once weekly)-treated ORX rats (n = 8-9 each) were killed 2 months after Surgery. Vehicle-treated ORX rats showed lower seminal vesicle weight, loss of proximal tibial trabecular bone mineral density, and reduced cortical thickness at the tibial shaft as measured by peripheral quantitative computed tomography relative to SHAM controls. Bone loss in vehicle-treated ORX rats was associated with enhanced bone turnover as evidenced by increases in tibial cancellous bone formation rate, osteoclast numbers, urinary excretion of calcium and deoxypyridinoline, and serum osteocalcin. T treatment of ORX rats restored seminal vesicle weight to SHAM control levels, and completely protected against post-ORX bone loss by suppressing bone turnover. Free sRANKL concentrations in bone marrow supernatants harvested from the Proximal femur were about 3-fold higher in vehicle-treated ORX relative to SHAM rats, and returned to SHAM control levels in T-treated ORX rats. mRNA abundance Of Matrix metalloproteinase-14 (MMP-14) in bone marrow was 4-fold higher in vehicle-treated ORX rats relative to SHAM rats. T treatment of ORX rats suppressed MMP-14 mRNA expression to SHAM control levels. We conclude that orchiectomy increases the concentration of free sRANKL in bone marrow of aged rats. In addition, increased shedding of membrane-bound RANKL by MMP-14 may be a pivotal mechanism resulting in augmented free sRANKL concentrations in the bone marrow environment after androgen withdrawal. (c) 2009 Elsevier Inc. All rights reserved.