Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan.
Int J Mol Sci. 2022 Jul 5;23(13):7485. doi: 10.3390/ijms23137485.
The crucial roles of dermatan sulfate (DS) have been demonstrated in tissue development of the cutis, blood vessels, and bone through construction of the extracellular matrix and cell signaling. Although DS classically exerts physiological functions via interaction with collagens, growth factors, and heparin cofactor-II, new functions have been revealed through analyses of human genetic disorders as well as of knockout mice with loss of DS-synthesizing enzymes. Mutations in human genes encoding the epimerase and sulfotransferase responsible for the biosynthesis of DS chains cause connective tissue disorders including spondylodysplastic type Ehlers-Danlos syndrome, characterized by skin hyperextensibility, joint hypermobility, and tissue fragility. DS-deficient mice show perinatal lethality, skin fragility, vascular abnormalities, thoracic kyphosis, myopathy-related phenotypes, acceleration of nerve regeneration, and impairments in self-renewal and proliferation of neural stem cells. These findings suggest that DS is essential for tissue development in addition to the assembly of collagen fibrils in the skin, and that DS-deficient knockout mice can be utilized as models of human genetic disorders that involve impairment of DS biosynthesis. This review highlights a novel role of DS in tissue development studies from the past decade.
硫酸皮肤素（DS）在构建细胞外基质和细胞信号转导方面，对皮肤、血管和骨骼的组织发育起着至关重要的作用。尽管 DS 经典地通过与胶原蛋白、生长因子和肝素辅因子-II 的相互作用发挥生理功能，但通过对人类遗传疾病的分析以及缺乏 DS 合成酶的敲除小鼠的研究，揭示了其新的功能。负责 DS 链生物合成的差向异构酶和硫酸转移酶编码人类基因的突变导致结缔组织疾病，包括脊柱骨骺发育不良型埃勒斯-当洛斯综合征，其特征为皮肤过度伸展、关节过度活动和组织脆弱。DS 缺乏型小鼠表现出围产期致死性、皮肤脆弱性、血管异常、胸椎后凸、与肌病相关的表型、神经再生加速以及神经干细胞自我更新和增殖受损。这些发现表明，DS 除了在皮肤中组装胶原蛋白原纤维外，对于组织发育也是必不可少的，并且 DS 缺乏型敲除小鼠可被用作涉及 DS 生物合成受损的人类遗传疾病的模型。本文综述了过去十年中 DS 在组织发育研究中的新作用。
