Sato Emi, Zhang Ling-Juan, Dorschner Robert A, Adase Christopher A, Choudhury Biswa P, Gallo Richard L
Department of Dermatology, University of California-San Diego, La Jolla, California, USA.
Glycotechnology Core Resource, University of California-San Diego, La Jolla, California, USA.
J Invest Dermatol. 2017 Aug;137(8):1774-1783. doi: 10.1016/j.jid.2017.03.034. Epub 2017 Apr 26.
In this study, we report that TIP39, a parathyroid hormone ligand family member that was recently identified to be expressed in the skin, can induce decorin expression and enhance wound repair. Topical treatment of mice with TIP39 accelerated wound repair, whereas TIP39-deficient mice had delayed repair that was associated with formation of abnormal collagen bundles. To study the potential mechanism responsible for the action of TIP39 in the dermis, fibroblasts were cultured in three-dimensional collagen gels, a process that results in enhanced decorin expression unless activated to differentiate to adipocytes, whereupon these cells reduce expression of several proteoglycans, including decorin. Small interfering RNA-mediated silencing of parathyroid hormone 2 receptor (PTH2R), the receptor for TIP39, suppressed the expression of extracellular matrix-related genes, including decorin, collagens, fibronectin, and matrix metalloproteases. Skin wounds in TIP39 mice had decreased decorin expression, and addition of TIP39 to cultured fibroblasts induced decorin and increased phosphorylation and nuclear translocation of CREB. Fibroblasts differentiated to adipocytes and treated with TIP39 also showed increased decorin and production of chondroitin sulfate. Furthermore, the skin of PTH2R mice showed abnormal extracellular matrix structure, decreased decorin expression, and skin hardness. Thus, the TIP39-PTH2R system appears to be a previously unrecognized mechanism for regulation of extracellular matrix formation and wound repair.
在本研究中，我们报告称，TIP39是甲状旁腺激素配体家族成员，最近被确定在皮肤中表达，它可诱导核心蛋白聚糖的表达并促进伤口修复。用TIP39对小鼠进行局部治疗可加速伤口修复，而缺乏TIP39的小鼠伤口修复延迟，这与异常胶原束的形成有关。为了研究TIP39在真皮中发挥作用的潜在机制，将成纤维细胞培养在三维胶原凝胶中，此过程会导致核心蛋白聚糖表达增强，除非被激活分化为脂肪细胞，此时这些细胞会降低包括核心蛋白聚糖在内的几种蛋白聚糖的表达。小干扰RNA介导的甲状旁腺激素2受体（PTH2R）（TIP39的受体）沉默抑制了包括核心蛋白聚糖、胶原蛋白、纤连蛋白和基质金属蛋白酶在内的细胞外基质相关基因的表达。TIP39基因敲除小鼠的皮肤伤口中核心蛋白聚糖表达降低，向培养的成纤维细胞中添加TIP39可诱导核心蛋白聚糖表达，并增加CREB的磷酸化和核转位。分化为脂肪细胞并用TIP39处理的成纤维细胞也显示核心蛋白聚糖增加以及硫酸软骨素生成增加。此外，PTH2R基因敲除小鼠的皮肤显示细胞外基质结构异常、核心蛋白聚糖表达降低以及皮肤硬度增加。因此，TIP39-PTH2R系统似乎是一种先前未被认识的调节细胞外基质形成和伤口修复的机制。
