Hyaluronate fragments reverse skin atrophy by a CD44-dependent mechanism.
Hyaluronate fragments reverse skin atrophy by a CD44-dependent mechanism.
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透明质酸片段通过CD44依赖性机制反向皮肤萎缩。
DOI：
10.1371/journal.pmed.0030493
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发表时间：
2006-12
期刊：
影响因子：
15.8
通讯作者：
Saurat, Jean-Hilaire
中科院分区：
文献类型：
--
作者：
Kaya, Guerkan;Tran, Christian;Sorg, Olivier;Hotz, Raymonde;Grand, Denise;Carraux, Pierre;Didierjean, Liliane;Stamenkovic, Ivan;Saurat, Jean-Hilaire
皮肤萎缩是衰老的常见表现，经常伴有溃疡和伤口愈合延迟。随着患者人口的日益老龄化，皮肤萎缩的管理正在成为临床的主要挑战，特别是考虑到目前没有有效的治疗选择。萎缩性皮肤显示透明质酸（HA）含量和主要细胞表面透明质酸受体CD44的表达减少。为了开发一种治疗皮肤萎缩的策略，我们研究了局部给药大小确定的HA片段（HAF）对皮肤营养的影响。用中等大小的HAF（卡扎菲；50,000 - 400,000 Da）而不是小尺寸HAF （HAFs; <50,000 Da）或大尺寸HAF （HAFl; >400,000 Da）处理原代角质细胞培养物诱导野生型（wt）而不是CD44缺陷（CD44−/−）角质细胞增殖。局部应用卡扎菲可引起wt小鼠明显表皮增生，而CD44 - / -小鼠无明显表皮增生，年龄或皮质类固醇相关皮肤萎缩患者皮肤明显增厚。针对肝素结合表皮生长因子（HB-EGF）及其受体erbB1的抗体和组织金属蛋白酶-3 （TIMP-3）抑制剂消除了卡扎菲对角质形成细胞增殖的影响。我们的观察结果为HA寡糖诱导角质细胞增殖提供了一种新的cd44依赖机制，并表明局部应用卡扎菲可能为人类皮肤萎缩提供一种有吸引力的治疗选择。小鼠和人类数据表明，局部应用中等大小的透明质酸碎片具有治疗皮肤萎缩的潜力。随着时间的流逝，人的身体会发生许多变化，但皮肤是衰老的第一个明显迹象——皱纹——发生的地方。皮肤主要由三层组成。最外层是表皮。它是一张纸的厚度，形成一个屏障，防止身体失去水分或感染因子进入。表皮细胞主要是角质形成细胞。这些特化的皮肤细胞在表皮底部不断产生。从那里，它们移动到皮肤表面，在那里它们脱落。中间层是真皮层。它比表皮厚约10倍，含有滋养皮肤、神经、皮脂腺和毛囊的血管。最后，皮下层包含汗腺，一些毛囊，血管和脂肪。真皮含有支撑皮肤的胶原纤维和提供弹性的弹性蛋白纤维。人的皮肤在成年早期开始衰老。到一个人80岁的时候，由于角质细胞增殖减少，他们的表皮厚度可能只有原来的一半。真皮也变薄，胶原蛋白和弹性蛋白纤维的损失意味着皮肤变得缺乏弹性。表皮和真皮层的逐渐丧失——皮肤萎缩——在临床上很重要，因为老化的皮肤比年轻的皮肤更脆弱，愈合速度更慢，也容易溃烂。没有人知道为什么皮肤萎缩会发生，但随着人们寿命的延长，它变得越来越普遍，而且没有有效的治疗方法。萎缩性皮肤的一个特征是，与正常皮肤相比，它含有更少的透明质酸（也称为透明质酸和透明质酸）——一种细胞外基质（包围细胞的物质）的主要碳水化合物成分。它也含有较少的CD44，一种与透明质酸相互作用的细胞表面蛋白。这种相互作用可以刺激细胞增殖和迁移。鉴于这些观察结果，在这项研究中，研究人员已经研究了用透明质酸碎片治疗萎缩的皮肤是否可以对抗萎缩。研究人员从正常小鼠和CD44缺失小鼠（CD44 - / -小鼠）中分离出角质形成细胞，并用不同大小的透明质酸片段处理它们。中等大小的透明质酸碎片（所谓的卡扎菲），而不是大或小碎片增加正常角质形成细胞的增殖，而不是CD44 - / -角质形成细胞。这表明对卡扎菲反应的增殖是cd44依赖性的。同样，将卡扎菲乳膏涂在正常小鼠的背部会导致表皮层增厚，但对CD44 - / -小鼠没有影响。最后，局部应用卡扎菲一个月导致6名皮肤萎缩患者皮肤增厚和临床改善，但对正常人皮肤没有影响。在接受治疗的患者中，真皮的胶原蛋白、弹性纤维和血管含量也有所增加。通过使用抗体阻断各种蛋白质的功能，研究人员还发现肝素结合表皮生长因子（HB-EGF，一种刺激角质形成细胞增殖的蛋白质）、erbB1（一种结合HB-EGF的细胞表面蛋白质）和基质金属蛋白酶（激活HB-EGF的蛋白质）都是通过HAFi刺激角质形成细胞增殖所必需的。综上所述，这些结果首次表明，将卡扎菲应用于萎缩性皮肤可能是有效的治疗方法。对正常人类皮肤没有任何影响是令人放心的，但考虑到正常小鼠皮肤增厚，这令人困惑，因此在透明质酸碎片用于临床之前，这一发现需要得到证实。还需要对更多的人进行更长时间的试验，以充分表征临床效果。最后，透明质酸片的作用机理有待进一步深入研究。这些研究可能会揭示治疗皮肤萎缩的其他潜在治疗选择。请通过本摘要的在线版本http://dx.doi.org/10.1371/journal.pmed.0030493访问这些网站。MedlinePlus百科全书关于皮肤衰老变化的条目美国国家衰老研究所，皮肤护理和衰老的患者信息美国皮肤病学会，皮肤衰老的患者信息CD44透明质酸受体的信息，由糖生物学维基百科关于皮肤和透明质酸的页面提供（注意，维基百科是一个免费的在线百科全书，任何人都可以编辑）
Skin atrophy is a common manifestation of aging and is frequently accompanied by ulceration and delayed wound healing. With an increasingly aging patient population, management of skin atrophy is becoming a major challenge in the clinic, particularly in light of the fact that there are no effective therapeutic options at present. Atrophic skin displays a decreased hyaluronate (HA) content and expression of the major cell-surface hyaluronate receptor, CD44. In an effort to develop a therapeutic strategy for skin atrophy, we addressed the effect of topical administration of defined-size HA fragments (HAF) on skin trophicity. Treatment of primary keratinocyte cultures with intermediate-size HAF (HAFi; 50,000–400,000 Da) but not with small-size HAF (HAFs; <50,000 Da) or large-size HAF (HAFl; >400,000 Da) induced wild-type (wt) but not CD44-deficient (CD44−/−) keratinocyte proliferation. Topical application of HAFi caused marked epidermal hyperplasia in wt but not in CD44−/− mice, and significant skin thickening in patients with age- or corticosteroid-related skin atrophy. The effect of HAFi on keratinocyte proliferation was abrogated by antibodies against heparin-binding epidermal growth factor (HB-EGF) and its receptor, erbB1, which form a complex with a particular isoform of CD44 (CD44v3), and by tissue inhibitor of metalloproteinase-3 (TIMP-3). Our observations provide a novel CD44-dependent mechanism for HA oligosaccharide-induced keratinocyte proliferation and suggest that topical HAFi application may provide an attractive therapeutic option in human skin atrophy. Mouse and human data suggest that topical application of intermediate-size hyaluronate fragments holds therapeutic potential for skin atrophy. Time wreaks many changes in the human body but the skin is where one of the first visible signs of aging—wrinkles—occurs. The skin consists of three main layers. The outermost layer is the epidermis. It is the thickness of a sheet of paper and forms a barrier that prevents the body losing water or infectious agents entering it. The cells in the epidermis are mainly keratinocytes. These specialized skin cells are continually produced at the base of the epidermis. From there, they move toward the skin's surface where they are shed. The middle layer is the dermis. It is about ten times thicker than the epidermis and contains the blood vessels that feed the skin, nerves, sebaceous glands, and hair follicles. The final, subcutaneous layer contains sweat glands, some hair follicles, blood vessels and fat. The dermis contains collagen fibers that support the skin and elastin fibers that provide flexibility. Human skin begins to age in early adulthood. By the time a person is 80 years old, their epidermis may be half its original thickness because of decreased keratinocyte proliferation. The dermis also thins, and loss of collagen and elastin fibers means that the skin becomes less elastic. The gradual loss of epidermis and dermis—skin atrophy—is clinically important because aging skin is more fragile and heals slower than young skin and is also prone to ulceration. No one knows why skin atrophy occurs, but it is becoming more common as people live longer, and there is no effective treatment for it. One characteristic of atrophic skin is that, compared to normal skin, it contains less hyaluronate (also called hyaluronan and hyaluronic acid)—a large carbohydrate component of the extracellular matrix, the material that surrounds cells. It also contains less CD44, a cell-surface protein that interacts with hyaluronate. This interaction can stimulate cell proliferation and migration. Given these observations, in this study the researchers have investigated whether treating atrophic skin with fragments of hyaluronate might counteract atrophy. The researchers isolated keratinocytes from normal mice and from CD44-deficient mice (CD44−/− mice) and treated them with different sized fragments of hyaluronate. Intermediate sized hyaluronate fragments (so-called HAFi) but not large or small fragments increased the proliferation of normal keratinocytes but not CD44−/− keratinocytes. This suggests that proliferation in response to HAFi is CD44-dependent. Similarly, a cream of HAFi applied to the backs of normal mice caused thickening of the epidermal layer but had no effect on CD44−/− mice. Finally, topical application of HAFi for one month caused skin thickening and clinical improvement in six people with skin atrophy but had no effect on normal human skin. The collagen, elastic fiber, and blood vessel content of the dermis also increased in treated patients. By using antibodies to block the function of various proteins, the researchers also discovered that heparin-binding epidermal growth factor (HB-EGF, a protein that stimulates keratinocyte proliferation), erbB1 (a cell-surface protein that binds HB-EGF), and matrix metalloproteinases (proteins that activate HB-EGF) are all required for the stimulation of keratinocyte proliferation by HAFi. Taken together, these results provide the first indication that application of HAFi to atrophic skin might be useful therapeutically. The absence of any effect on normal human skin is reassuring but puzzling given the thickening seen in normal mouse skin, so this finding needs confirmation before hyaluronate fragments are used clinically. Longer trials in more people are also needed to characterize the clinical effects fully. Finally, the mechanism by which hyaluronate fragments have their effect needs to be studied in more depth. Such studies might reveal other potential therapeutic options for the treatment of skin atrophy. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030493. MedlinePlus encyclopedia entry on aging changes in skin US National Institute on Aging, patient information on skin care and aging American Academy of Dermatology, patient information on aging skin Information on CD44, the hyaluronan receptor, provided by Glycoforum a source of information on glycobiology Wikpedia pages on skin and on hyaluronan (note that Wikipedia is a free online encyclopedia that anyone can edit)
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影响因子：
10.5
作者：
Yu, WH;Woessner, JF;Stamenkovic, I
通讯作者：
Stamenkovic, I
DOI：
10.1083/jcb.150.5.1071
发表时间：
2000-09-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Sherman LS;Rizvi TA;Karyala S;Ratner N
通讯作者：
Ratner N
DOI：
10.1083/jcb.140.2.431
发表时间：
1998-01-26
期刊：
The Journal of cell biology
影响因子：
--
作者：
Skelton TP;Zeng C;Nocks A;Stamenkovic I
通讯作者：
Stamenkovic I
影响因子：
6.5
作者：
Dokka, S;Cooper, SR;Karras, JG
通讯作者：
Karras, JG
影响因子：
4.8
作者：
LAURENT, TC;FRASER, JRE
通讯作者：
FRASER, JRE