Department of Dermatology and Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California, USA.
J Clin Invest. 2011 Nov;121(11):4348-61. doi: 10.1172/JCI46475. Epub 2011 Oct 24.
Wounds that fail to heal in a timely manner, for example, diabetic foot ulcers, pose a health, economic, and social problem worldwide. For decades, conventional wisdom has pointed to growth factors as the main driving force of wound healing; thus, growth factors have become the center of therapeutic developments. To date, becaplermin (recombinant human PDGF-BB) is the only US FDA-approved growth factor therapy, and it shows modest efficacy, is costly, and has the potential to cause cancer in patients. Other molecules that drive wound healing have therefore been sought. In this context, it has been noticed that wounds do not heal without the participation of secreted Hsp90α. Here, we report that a 115-aa fragment of secreted Hsp90α (F-5) acts as an unconventional wound healing agent in mice. Topical application of F-5 peptide promoted acute and diabetic wound closure in mice far more effectively than did PDGF-BB. The stronger effect of F-5 was due to 3 properties not held by conventional growth factors: its ability to recruit both epidermal and dermal cells; the fact that its ability to promote dermal cell migration was not inhibited by TGF-β; and its ability to override the inhibitory effects of hyperglycemia on cell migration in diabetes. The discovery of F-5 challenges the long-standing paradigm of wound healing factors and reveals a potentially more effective and safer agent for healing acute and diabetic wounds.
未能及时愈合的伤口，例如糖尿病足溃疡，在全球范围内构成了健康、经济和社会问题。几十年来，传统观点认为生长因子是伤口愈合的主要驱动力；因此，生长因子已成为治疗开发的中心。迄今为止，becaplermin（重组人 PDGF-BB）是唯一获得美国 FDA 批准的生长因子疗法，其疗效有限，价格昂贵，并有在患者中引发癌症的潜力。因此，人们一直在寻找其他促进伤口愈合的分子。在这种情况下，人们注意到没有分泌的 Hsp90α 参与，伤口就无法愈合。在这里，我们报告说，分泌的 Hsp90α 的 115 个氨基酸片段（F-5）在小鼠中作为一种非传统的伤口愈合剂发挥作用。F-5 肽的局部应用能更有效地促进小鼠的急性和糖尿病性伤口闭合，比 PDGF-BB 效果强得多。F-5 的更强效果归因于 3 种常规生长因子不具备的特性：它招募表皮和真皮细胞的能力；其促进真皮细胞迁移的能力不受 TGF-β抑制的事实；以及它能够克服高血糖对糖尿病中细胞迁移的抑制作用。F-5 的发现挑战了伤口愈合因子的长期范例，并揭示了一种更有效和更安全的治疗急性和糖尿病性伤口的药物。
