Androgen prevents hypogonadal bone loss via inhibition of resorption mediated by mature osteoblasts/osteocytes.
Androgen prevents hypogonadal bone loss via inhibition of resorption mediated by mature osteoblasts/osteocytes.
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DOI：
10.1016/j.bone.2012.08.111
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发表时间：
2012-11
期刊：
影响因子：
4.1
通讯作者：
Iwaniec, Urszula T.
中科院分区：
文献类型：
--
作者：
Wiren, Kristine M.;Zhang, Xiao-Wei;Olson, Dawn A.;Turner, Russell T.;Iwaniec, Urszula T.
雄激素受体（AR）在整个成骨细胞谱系中表达。两种不同的AR转基因家族（AR2.3-tg和AR3.6-tg小鼠）表现出重叠和不同的表达谱，用于评估增强雄激素敏感性对改善性腺功能减退的影响。两种不同的范式类固醇替代后，睾丸切除术（ORX）被用作预防或治疗性治疗。在雄性野生型（WT）、AR 2.3-tg和AR 3.6-tg小鼠中，在5个月时立即进行DHT替代（预防，更高的转换）或在3个月时延迟2个月进行DHT治疗（治疗，更低的转换），两种小鼠均在最后6周进行治疗。进行双能X线吸收测定法（DXA）、显微计算机断层扫描（μCT）和组织形态计量学检查。在预防模型中，与假手术组相比，ORX显著降低了所有基因型的BMD和BMC，而DHT在预防骨质减少方面有效。在治疗模型中，与假手术相比，所有基因型都变得骨质减少，但在长期性腺功能减退期后，延迟DHT治疗几乎没有益处。所有基因型的中段总骨μCT分析通常显示ORX后减少。延迟DHT在任何基因型中恢复骨体积无效，而立即治疗仅在AR转基因小鼠中防止损失。皮质厚度也随着ORX而降低，但立即DHT处理仅在WT小鼠中有效增加厚度，这可能是由于两种AR-tg系中骨髓体积的扩张。在代谢高度活跃的松质骨中，ORX导致所有基因型的骨体积/组织体积（BV/TV）降低，在3个测量部位一致。再次延迟治疗，有一点效果的DHT恢复BV/TV，但当在ORX的时间，DHT完全防止了所有基因型的松质骨减少。与WT相比，在AR转基因系中，观察到使用即时DHT替代的松质骨结构的改善。相比之下，在所有基因型使用延迟治疗的范例只有适度的变化。在两种模式中使用ORX，小梁数量减少，而间距增加。因此，雄激素治疗主要通过其抗再吸收特性有效预防骨内膜和松质骨减少，但作为恢复骨的治疗策略几乎没有合成代谢作用。考虑到两种AR转基因系对雄激素处理的反应相似，重叠的表达谱表明体内介导雄激素作用的靶细胞是成熟的成骨细胞/骨细胞。总之，这些结果表明，在成年小鼠中，雄激素治疗可以减少骨吸收，但几乎没有整体合成代谢活性。
Androgen receptor (AR) is expressed throughout the osteoblast lineage. Two different AR transgenic families (AR2.3-tg and AR3.6-tg mice) demonstrating overlapping and distinct expression profiles were employed to assess the effects of enhanced androgen sensitivity to ameliorate hypogonadal loss. Two different paradigms of steroid replacement following orchidectomy (ORX) were used as either preventative or therapeutic therapy. ORX was performed in male wild-type (WT), AR2.3-tg and AR3.6-tg mice at 5 months with immediate DHT replacement (prevention, higher turnover) or at 3 months with DHT treatment delayed for 2 months (therapeutic, lower turnover), both with treatment for the last 6 weeks. Dual energy x-ray absorptiometry (DXA), microcomputed tomography (μCT), and histomorphometry were performed. In the prevention model, ORX significantly reduced BMD and BMC in all genotypes compared to sham and DHT was effective at prevention of osteopenia. In the therapeutic model, all genotypes became osteopenic compared to sham, but after a prolonged hypogonadal period, delayed DHT treatment provided little benefit. μCT analysis of mid-shaft total bone in all genotypes generally showed reductions after ORX. Delayed DHT was ineffective at restoring bone volume in any genotype whereas immediate treatment prevented loss only in AR transgenic mice. Cortical thickness also decreased with ORX but immediate DHT treatment was effective to increase thickness only in WT mice, likely due to expansion of marrow volume in both AR-tg lines. In metabolically highly active cancellous bone, ORX resulted in lower bone volume/tissue volume (BV/TV) in all genotypes, consistent among 3 sites measured. Again with delayed treatment, there was little effect of DHT to restore BV/TV, but when administered at the time of ORX, DHT completely prevented the decrease in cancellous bone in all genotypes. Improvement in cancellous bone architecture was seen with immediate DHT replacement that was enhanced in AR transgenic lines compared to WT. In contrast, there were only modest changes in all genotypes using the delayed treatment paradigm. With ORX in both paradigms, trabecular number was decreased while spacing increased. Thus, androgen therapy is effective for the prevention of endosteal and cancellous osteopenia primarily through its anti-resorptive properties, but shows little anabolic action as a therapeutic strategy to restore bone. Given the similarity in response to androgen treatment in both AR transgenic lines, overlapping expression profiles suggest that the target cells mediating androgen action in vivo are mature osteoblast/osteocytes. Combined, these results demonstrate that in the adult mouse, androgen treatment can reduce bone resorption but has little overall anabolic activity.
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影响因子：
6.2
作者：
Notini, Amanda J.;McManus, Julie F.;Davey, Rachel A.
通讯作者：
Davey, Rachel A.
影响因子：
15.9
作者：
Falahati-Nini, A;Riggs, BL;Khosla, S
通讯作者：
Khosla, S
DOI：
10.1084/jem.20021017
发表时间：
2002-11-18
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Liegibel UM;Sommer U;Tomakidi P;Hilscher U;Van Den Heuvel L;Pirzer R;Hillmeier J;Nawroth P;Kasperk C
通讯作者：
Kasperk C
影响因子：
5.8
作者：
Rosner, William;Auchus, Richard J.;Raff, Hershel
通讯作者：
Raff, Hershel
影响因子：
3.6
作者：
Ma, J;Graves, J;Zeldin, DC
通讯作者：
Zeldin, DC