Laboratory of Connective Tissues Biology, GIGA-R, University of Liege, 4000 Sart Tilman, Belgium.
Laboratory of Hematology, GIGA-R, University of Liege, 4000 Sart Tilman, Belgium.
Matrix Biol. 2018 Sep;70:140-157. doi: 10.1016/j.matbio.2018.04.002. Epub 2018 Apr 9.
Since its first description, ADAMTS14 has been considered as an aminoprocollagen peptidase based on its high similarity with ADAMTS3 and ADAMTS2. As its importance for procollagen processing was never experimentally demonstrated in vivo, we generated Adamts14-deficient mice. They are healthy, fertile and display normal aminoprocollagen processing. They were further crossed with Adamts2-deficient mice to evaluate potential functional redundancies between these two highly related enzymes. Initial characterizations made on young Adamts2-Adamts14-deficient animals showed the same phenotype as that of Adamts2-deficient mice, with no further reduction of procollagen processing and no significant aggravation of the structural alterations of collagen fibrils. However, when evaluated at older age, Adamts2-Adamts14-deficient mice surprisingly displayed epidermal lesions, appearing in 2 month-old males and later in some females, and then worsening rapidly. Immunohistological evaluations of skin sections around the lesions revealed thickening of the epidermis, hypercellularity in the dermis and extensive infiltration by immune cells. Additional investigations, performed on young mice before the formation of the initial lesions, revealed that the primary cause of the phenotype was not related to alterations of the epidermal barrier but was rather the result of an abnormal activation and differentiation of T lymphocytes towards a Th1 profile. However, the primary molecular defect probably does not reside in the immune system itself since irradiated Adamts2-Adamts14-deficient mice grafted with WT immune cells still developed lesions. While originally created to better characterize the common and specific functions of ADAMTS2 and ADAMTS14 in extracellular matrix and connective tissues homeostasis, the Adamts2-Adamts14-deficient mice revealed an unexpected but significant role of ADAMTS in the regulation of immune system, possibly through a cross-talk involving mesenchymal cells and the TGFβ pathways.
自首次描述以来，ADAMTS14 一直被认为是一种氨基脯氨酸胶原肽酶，因为它与 ADAMTS3 和 ADAMTS2 高度相似。由于其在体内对前胶原加工的重要性从未得到实验证明，我们生成了 Adamts14 缺陷型小鼠。它们健康、有生育能力，并且表现出正常的氨基前胶原加工。它们进一步与 Adamts2 缺陷型小鼠杂交，以评估这两种高度相关的酶之间是否存在潜在的功能冗余。对年轻的 Adamts2-Adamts14 缺陷型动物进行的初步特征分析显示，其表型与 Adamts2 缺陷型小鼠相同，前胶原加工没有进一步减少，胶原纤维的结构改变也没有明显加重。然而，当在老年时进行评估时，令人惊讶的是，Adamts2-Adamts14 缺陷型小鼠表现出表皮病变，2 月龄雄性小鼠中出现，随后一些雌性小鼠中出现，然后迅速恶化。对病变周围皮肤切片的免疫组织学评估显示表皮增厚、真皮细胞增多和大量免疫细胞浸润。在最初病变形成之前对年轻小鼠进行的进一步研究表明，该表型的主要原因与表皮屏障的改变无关，而是由于 T 淋巴细胞向 Th1 表型的异常激活和分化。然而，主要的分子缺陷可能不在免疫系统本身，因为辐照的 Adamts2-Adamts14 缺陷型小鼠移植 WT 免疫细胞后仍会出现病变。虽然最初创建这些小鼠是为了更好地描述 ADAMTS2 和 ADAMTS14 在细胞外基质和结缔组织稳态中的共同和特定功能，但 Adamts2-Adamts14 缺陷型小鼠揭示了 ADAMTS 在免疫系统调节中的一个意外但重要的作用，可能通过涉及间充质细胞和 TGFβ 途径的串扰。
