Role of heparan sulfate 6-0 endosulfatases in intervertebral disc homeostasis.
Role of heparan sulfate 6-0 endosulfatases in intervertebral disc homeostasis.
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DOI：
10.14670/hh-18-107
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发表时间：
2019-03
影响因子：
2
通讯作者：
S. Otsuki;O. Alvarez-Garcia;M. Lotz;M. Neo
中科院分区：
文献类型：
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作者：
S. Otsuki;O. Alvarez-Garcia;M. Lotz;M. Neo
研究硫酸乙酰肝素内切硫酸酯酶（Sulfs）在椎间盘（IVD）中的表达，以阐明其在IVD体内平衡中的作用。Sulf-1和-2在正常和退化的人IVD中的表达被阐明。在野生型（WT）和Sulf-1基因敲除（Sulf-1 β/β）小鼠的IVD中分析了Sulf表达、II型胶原蛋白水平和结构变化的ESTA相关影响。检测重组Sulf-1（100 ng/ml）和Sulf-1敲低对ATDC 5细胞中硫酸乙酰肝素蛋白聚糖和胶原表达的影响。最后，评估Sulf-1对转化生长因子（TGF）β1诱导的信号传导的影响。结果表明，Sulf-1和-2水平在退化的人IVD中更高。在WT小鼠中，Sulf-1和-2表达通常随着动物年龄的增长而下降。特别是，髓核中的Sulf-1在1个月和6个月时高于Sulf-2，并随着年龄的增长而显著下降。Sulf-1-/-小鼠表现出比WT小鼠更严重的IVD病理，髓核中II型胶原水平较低，纤维环中I型胶原变性。在体外，Sulf-1诱导ATDC 5细胞中II型胶原表达，并显著增加TGF-β1诱导的Smad 2/3磷酸化。总之，Sulf-1可能通过调节胶原蛋白的表达，在IVD从发育到维持体内平衡过程中发挥关键作用。
The expression of heparan sulfate endosulfatases (Sulfs) was investigated in the intervertebral disc (IVD) to clarify their role in IVD homeostasis. Sulf-1 and -2 expression were elucidated in normal and degenerated human IVD. Age-related effects on Sulf expression, type II collagen levels, and structural changes were analyzed in IVDs of wild-type (WT) and Sulf-1 knockout (Sulf-1⁻/⁻) mice. The effect of recombinant Sulf-1 (100 ng/ml) and Sulf-1 knockdown on heparan sulfate proteoglycan and collagen expression in ATDC5 cells were examined. Finally, the effect of Sulf-1 on transforming growth factor (TGF) β1-induced signaling was evaluated. Results show that Sulf-1 and -2 levels were higher in degenerated human IVDs. In WT mice, Sulf-1 and -2 expression generally declined as the animals aged. In particular, Sulf-1 in the nucleus pulposus was higher compared with Sulf-2 at the age of 1 and 6 months and significantly declined with aging. Sulf-1-/- mice showed more severe IVD pathology than WT mice, with lower type II collagen levels in nucleus pulposus, and degeneration with type I collagen in annulus fibrosus. In vitro, Sulf-1 induced type II collagen expression and significantly increased TGF-β1-induced Smad2/3 phosphorylation in ATDC5 cells. In conclusion, Sulf-1 might play a critical role from development to maintenance of IVD homeostasis by regulating collagen expression.