Role of Smad3 in the hormonal modulation of in vivo wound healing responses
Role of Smad3 in the hormonal modulation of in vivo wound healing responses
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DOI：
10.1046/j.1524-475x.2003.11614.x
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发表时间：
2003-11-01
影响因子：
2.9
通讯作者：
Roberts, AB
中科院分区：
文献类型：
--
作者：
Ashcroft, GS;Mills, SJ;Roberts, AB
Smad 3参与介导转化生长因子-β超家族成员的细胞内信号传导，并在细胞增殖、分化、迁移和对皮肤伤口愈合至关重要的基质的加工中起关键作用。Smad 3和激素信号之间的体外串扰已被认为是调节细胞活性的重要控制机制;然而，其在体内的相关性尚不清楚。在这里，我们报告说，Smad 3在雄激素介导的抑制伤口愈合中发挥作用，但在体内雌激素调节的反应。野生型和Smad 3基因缺失的雌性小鼠在卵巢切除术后均表现出延迟愈合，这可以通过雌激素替代来逆转。相比之下，去势加速了野生型雄性小鼠的愈合，并且通过外源性雄激素治疗是可逆的。有趣的是，雄激素水平的调节导致Smad 3基因敲除小鼠的愈合反应没有明显的扰动。突变的单核细胞可以被脂多糖刺激，以类似于野生型细胞的方式产生特定的促炎剂（巨噬细胞单核细胞抑制因子），但对雄激素介导的刺激表现出沉默的反应，同时保持对雌激素诱导的巨噬细胞抑制因子抑制的正常反应。这些数据表明，Smad 3在正常伤口愈合反应过程中介导雄激素信号传导中起作用，并暗示Smad 3在雄激素对炎症细胞活性的调节中起作用。
Smad3 is involved in mediating intracellular signaling by members of the transforming growth factor-beta superfamily and plays a critical role in the cellular proliferation, differentiation, migration, and elaboration of matrix pivotal to cutaneous wound healing. Cross-talk between Smad3 and hormone signaling in vitro has been suggested as an important control mechanism regulating cell activities; however, its relevance in vivo is unknown. Here we report that Smad3 plays a role in androgen-mediated inhibition of wound healing but not in the responses to estrogen modulation in vivo. Both wild-type and Smad3 null female mice exhibited delayed healing following ovariectomy, which could be reversed by estrogen replacement. By contrast, castration accelerated healing in wild-type male mice and was reversible by exogenous androgen treatment. Intriguingly, modulation of androgen levels resulted in no discernible perturbation in the healing response in the Smad3 null mice. Mutant monocytes could be lipopolysaccharide stimulated to produce specific pro-inflammatory agents (macrophage monocyte inhibitory factor) in a fashion similar to wild-type cells, but exhibited a muted response to androgen-mediated stimulation while maintaining a normal response to estrogen-induced macrophage inhibitory factor inhibition. These data suggest that Smad3 plays a role in mediating androgen signaling during the normal wound healing response and implicate Smad3 in the modulation of inflammatory cell activity by androgens.