Sinnesael Mieke, Jardi Ferran, Deboel Ludo, Laurent Michaël R, Dubois Vanessa, Zajac Jeffrey D, Davey Rachel A, Carmeliet Geert, Claessens Frank, Vanderschueren Dirk
Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; Gerontology and Geriatrics, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
Mol Cell Endocrinol. 2015 Aug 15;411:198-206. doi: 10.1016/j.mce.2015.04.030. Epub 2015 May 6.
Androgen deficiency or androgen receptor knockout (ARKO) causes high-turnover osteopenia, but the target cells for this effect remain unclear. To examine whether AR in osteoclasts directly suppresses bone resorption, we crossed AR-floxed with cathepsin K-Cre mice. Osteoclast-specific ARKO (ocl-ARKO) mice showed no changes neither in osteoclast surface nor in bone microarchitecture nor in the response to orchidectomy and androgen replacement, indicating that the AR in osteoclasts is not critical for bone maintenance. In line with the lack of a bone phenotype, the levels of AR were very low in osteoclast-enriched cultures derived from bone marrow (BM) and undetectable in osteoclasts generated from spleen precursors. Since tibiae of ubiquitous ARKO mice displayed increased osteoclast counts, the role of AR was further explored using cell cultures from these animals. Osteoclast generation and activity in vitro were similar between ARKO and wildtype control (WT) mice. In co-culture experiments, BM stromal cells (BMSCs) were essential for the suppressive action of AR on osteoclastogenesis and osteoclast activity. Stimulation with 1,25(OH)2 vitamin D3 increased Rankl and decreased Tnfsf11 (osteoprotegerin, Opg) gene expression in BMSCs more than in osteoblasts. This increase in the Rankl/Opg ratio following 1,25(OH)2D3 stimulation was lower, not higher, in ARKO mice. Runx2 expression in BMSCs was however higher in ARKO vs. WT, suggesting that ARKO mice may more readily commit osteoprogenitor cells to osteoblastogenesis. In conclusion, the AR does not seem to suppress bone resorption through direct actions in osteoclasts. BMSCs may however represent an alternative AR target in the BM milieu.
雄激素缺乏或雄激素受体敲除（ARKO）会导致高转换型骨质减少，但这种作用的靶细胞仍不清楚。为了研究破骨细胞中的雄激素受体（AR）是否直接抑制骨吸收，我们将携带floxed AR的小鼠与组织蛋白酶K-Cre小鼠进行杂交。破骨细胞特异性ARKO（ocl-ARKO）小鼠在破骨细胞表面、骨微结构以及对去势和雄激素替代的反应方面均无变化，这表明破骨细胞中的AR对骨维持并不关键。与缺乏骨表型一致，在源自骨髓（BM）的富含破骨细胞的培养物中，AR水平非常低，而在由脾前体细胞产生的破骨细胞中无法检测到。由于全身性ARKO小鼠的胫骨显示破骨细胞数量增加，因此使用这些动物的细胞培养物进一步探索了AR的作用。ARKO小鼠和野生型对照（WT）小鼠在体外破骨细胞的生成和活性方面相似。在共培养实验中，骨髓基质细胞（BMSC）对于AR对破骨细胞生成和破骨细胞活性的抑制作用至关重要。用1,25(OH)2维生素D3刺激后，BMSC中核因子κB受体活化因子配体（Rankl）的表达增加，骨保护素（Opg，Tnfsf11）基因的表达降低，且这种变化在BMSC中比在成骨细胞中更明显。在1,25(OH)2D3刺激后，ARKO小鼠中Rankl/Opg比值的增加较低，而非更高。然而，与WT小鼠相比，ARKO小鼠BMSC中Runx2的表达更高，这表明ARKO小鼠可能更容易使骨祖细胞向成骨细胞分化。总之，AR似乎并非通过直接作用于破骨细胞来抑制骨吸收。然而，BMSC可能是骨髓环境中AR的另一个作用靶点。
