Hanyang University Institute for Rheumatology Research, Seoul, Republic of Korea.
Division of Rheumatology, Department of Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Arthritis Res Ther. 2020 May 24;22(1):121. doi: 10.1186/s13075-020-02217-9.
Ankylosing spondylitis (AS) is characteristically male-predominant, and progressive spinal ankylosis affects male patients more severely; however, the hormonal effects in males with AS are poorly understood.
In the present study, the regulatory effects of dutasteride, a 5-α reductase inhibitor that blocks the conversion of testosterone to dihydrotestosterone (DHT), were examined in curdlan-administered male SKG mice to determine spinal bone formation, bone metabolism-related markers, and interleukin (IL)-17A cytokine and T cell populations. In addition, the effects of DHT on primary osteoprogenitors from the facet joints of AS patients were assessed based on osteoblast-related parameters. DHT level was measured, and the correlation with modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) was analyzed in AS patients.
In curdlan-administered SKG mice, dutasteride treatment resulted in an increased accumulation of hydroxyapatite in the spine which was positively correlated with serum IL-17A levels. In the analysis of bone metabolism-related molecules, a decrease in sclerostin levels was observed in the sera in the dutasteride group. Continuous exposure to DHT resulted in fewer calcium deposits in AS osteoprogenitors during osteoblast differentiation. DHT-treated AS osteoprogenitors showed decreased osteocalcin and increased DKK1 and SOST1 mRNA expression, supporting the results of the in vivo experiments. Treatment with dutasteride upregulated bone formation in the spine of curdlan-administered SKG mice and DHT treatment downregulated osteoblast differentiation in vitro.
Treatment with dutasteride affected the bone formation in the spine of curdlan-treated SKG mice, and DHT treatment attenuated osteoblast differentiation in vitro. Therefore, contrary to what could be expected if osteoblasts contributed to spinal ankylosis, DHT inhibition might increase rather than decrease the progression of spinal ankylosis despite the higher levels of DHT observed in many AS patients.
强直性脊柱炎（AS）以男性为主导，进行性脊柱融合会更严重影响男性患者；然而，男性 AS 中的激素影响仍知之甚少。
在本研究中，检查了 5α-还原酶抑制剂 dutasteride 的调节作用，该抑制剂可阻止睾酮转化为二氢睾酮（DHT），以确定软骨素给药的 SKG 雄性小鼠的脊柱骨形成、与骨代谢相关的标志物、白介素（IL）-17A 细胞因子和 T 细胞群。此外，根据成骨细胞相关参数评估 DHT 对 AS 患者关节突关节原代成骨细胞的作用。测定 AS 患者的 DHT 水平，并分析与改良 Stoke 强直性脊柱炎脊柱评分（mSASSS）的相关性。
在软骨素给药的 SKG 小鼠中， dutasteride 治疗导致脊柱中羟磷灰石的积累增加，这与血清 IL-17A 水平呈正相关。在与骨代谢相关分子的分析中， dutasteride 组血清中 sclerostin 水平下降。在成骨细胞分化过程中，DHT 的持续暴露导致 AS 成骨细胞中的钙沉积减少。DHT 处理的 AS 成骨细胞表现出骨钙素减少和 DKK1 和 SOST1 mRNA 表达增加，支持体内实验的结果。 dutasteride 治疗可上调软骨素给药 SKG 小鼠脊柱的骨形成，而 DHT 治疗可下调体外成骨细胞分化。
dutasteride 治疗影响软骨素处理的 SKG 小鼠脊柱的骨形成，DHT 治疗可减弱体外成骨细胞分化。因此，尽管许多 AS 患者的 DHT 水平较高，但与人们可能预期的相反，DHT 抑制可能会增加而不是减少脊柱融合的进展。
