Edmondson S R, Thumiger S P, Kaur P, Loh B, Koelmeyer R, Li A, Silha J V, Murphy L J, Wraight C J, Werther G A
Epithelial Stem Cell Biology Laboratory, Peter MacCallum Cancer Institute, East Melbourne, 3002 Victoria, Australia.
Br J Dermatol. 2005 Feb;152(2):225-30. doi: 10.1111/j.1365-2133.2004.06350.x.
The colocalization of insulin-like growth factor binding protein-3 (IGFBP-3) and IGF-I receptor (IGF-IR) in the basal/germinative layer of the epidermis suggests a key role in modulating epidermal homeostasis.
We aimed to clarify both the specific cellular localization and the effect of excess epidermal IGFBP-3 on keratinocyte proliferation.
(i) Total RNA was isolated from fluorescence-activated cell sorted basal human keratinocyte subtypes [keratinocyte stem cells, transit amplifying keratinocytes (TA), postmitotic differentiating keratinocytes (PMD)], and real-time polymerase chain reaction analysis was used to determine the abundance of IGFBP-3 and IGF-IR mRNAs. (ii) An IGFBP-3 transgenic mouse model was then used to assess the effect of excess epidermal IGFBP-3 on keratinocyte proliferation. Excess epidermal IGFBP-3 mRNA and protein was determined by in situ hybridization and immunohistochemistry, respectively.
(i) The highest levels of IGFBP-3 mRNA were detected in TA keratinocytes, in contrast to IGF-IR mRNA levels which were highest in PMD keratinocytes. (ii) Elevated human IGFBP-3 mRNA and protein was confirmed in the epidermis of skin derived from transgenic mice. Excess IGFBP-3 reduced the relative percentage of proliferative keratinocytes (Ki67 positive) irrespective of skin location (belly, back and tail). Thus, in the epidermis, IGFBP-3 mRNA is highly expressed by proliferative keratinocytes (TA) and overexpression of IGFBP-3 inhibits keratinocyte proliferation.
We conclude that in vivo IGFBP-3 ensures epidermal homeostasis via downregulation of keratinocyte proliferation, and thus modulates the early stages of keratinocyte differentiation.
胰岛素样生长因子结合蛋白-3（IGFBP-3）与IGF-I受体（IGF-IR）在表皮基底/生发层的共定位表明其在调节表皮稳态中起关键作用。
我们旨在明确IGFBP-3在特定细胞中的定位以及表皮中IGFBP-3过量对角质形成细胞增殖的影响。
（i）从经荧光激活细胞分选的人基底角质形成细胞亚型[角质形成干细胞、过渡扩增角质形成细胞（TA）、有丝分裂后分化角质形成细胞（PMD）]中分离总RNA，并采用实时聚合酶链反应分析来确定IGFBP-3和IGF-IR mRNA的丰度。（ii）然后使用IGFBP-3转基因小鼠模型评估表皮中IGFBP-3过量对角质形成细胞增殖的影响。分别通过原位杂交和免疫组织化学测定过量的表皮IGFBP-3 mRNA和蛋白。
（i）在TA角质形成细胞中检测到最高水平的IGFBP-3 mRNA，而IGF-IR mRNA水平在PMD角质形成细胞中最高。（ii）在转基因小鼠来源皮肤的表皮中证实了人IGFBP-3 mRNA和蛋白升高。无论皮肤部位（腹部、背部和尾部）如何，过量的IGFBP-3均降低了增殖角质形成细胞（Ki67阳性）的相对百分比。因此，在表皮中，IGFBP-3 mRNA在增殖角质形成细胞（TA）中高表达，IGFBP-3的过表达抑制角质形成细胞增殖。
我们得出结论，在体内IGFBP-3通过下调角质形成细胞增殖来确保表皮稳态，从而调节角质形成细胞分化的早期阶段。
