Regulation of sclerostin in glucocorticoid-induced osteoporosis (GIO) in mice and humans
Regulation of sclerostin in glucocorticoid-induced osteoporosis (GIO) in mice and humans
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DOI：
10.1530/ec-19-0104
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发表时间：
2019-07-01
影响因子：
2.9
通讯作者：
Rauner, Martina
中科院分区：
文献类型：
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作者：
Thiele, Sylvia;Hannemann, Anke;Rauner, Martina
糖皮质激素(GC)用于治疗炎症性疾病，包括各种形式的关节炎。然而，它们的使用受到限制，其中包括对骨骼的不利影响。最近发现Wnt和骨形成抑制因子skerostin参与了GC诱导的骨质疏松症的发病机制。然而，数据并不明确。这项研究的目的是使用几个高GC水平的小鼠模型和两个独立的GC治疗患者队列来评估GC对硬化素的调节。24周龄C57BL/6和18周龄DBA/1雄性小鼠暴露于GC和12周龄内源性皮质醇增高症小鼠，表现为骨形成减少，表现为P1NP水平下降和血清硬化素水平上升。然而，硬化素在股骨组织和GC处理的骨髓基质细胞中的表达并没有一致的变化。相反，GC剂量和时间依赖地抑制人间充质基质细胞中硬化素的mRNA和蛋白水平，并且这种作用依赖于GC受体。与人类细胞培养数据一致，暴露于GC的类风湿性关节炎(RA)和风湿性多肌痛(PMR)患者的血清硬化素水平低于年龄和性别匹配的健康对照组(分别为-40%和-26.5%，P<；0.001)。综上所述，硬化素在小鼠和人类中似乎受到GC的不同调控，因为它在人类中被GCs抑制，但在小鼠中并没有一致的改变。还需要进一步的研究来描述在小鼠和人类中GC调节硬化素的差异，并评估硬化素是否介导了GC诱导的人类骨质疏松症。
Glucocorticoids (GC) are used for the treatment of inflammatory diseases, including various forms of arthritis. However, their use is limited, amongst others, by adverse effects on bone. The Wnt and bone formation inhibitor sclerostin was recently implicated in the pathogenesis of GC-induced osteoporosis. However, data are ambiguous. The aim of this study was to assess the regulation of sclerostin by GC using several mouse models with high GC levels and two independent cohorts of patients treated with GC. Male 24-week-old C57BL/6 and 18-week-old DBA/1 mice exposed to GC and 12-week-old mice with endogenous hypercortisolism displayed reduced bone formation as indicated by reduced levels of P1NP and increased serum sclerostin levels. The expression of sclerostin in femoral bone tissue and GC-treated bone marrow stromal cells, however, was not consistently altered. In contrast, GC dose- and time-dependently suppressed sclerostin at mRNA and protein levels in human mesenchymal stromal cells, and this effect was GC receptor dependent. In line with the human cell culture data, patients with rheumatoid arthritis (RA, n = 101) and polymyalgia rheumatica (PMR, n = 21) who were exposed to GC had lower serum levels of sclerostin than healthy age- and sex-matched controls (-40%, P < 0.01 and -26.5%, P < 0.001, respectively). In summary, sclerostin appears to be differentially regulated by GC in mice and humans as it is suppressed by GCs in humans but is not consistently altered in mice. Further studies are required to delineate the differences between GC regulation of sclerostin in mice and humans and assess whether sclerostin mediates GC-induced osteoporosis in humans.