Division of Anatomy and Cell Biology of the Hard Tissue, Department of Tissue Regeneration and Reconstruction, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8514, Japan.
Department of Oral Functional Anatomy, Faculty of Dental Medicine, Hokkaido University, Sapporo, 060-8586, Japan.
Sci Rep. 2018 Nov 20;8(1):17134. doi: 10.1038/s41598-018-35412-5.
Chondroitin sulfate (CS) proteoglycan is a major component of the extracellular matrix and plays an important part in organogenesis. To elucidate the roles of CS for craniofacial development, we analyzed the craniofacial morphology in CS N-acetylgalactosaminyltransferase-1 (T1) gene knockout (KO) mice. T1KO mice showed the impaired intramembranous ossification in the skull, and the final skull shape of adult mice included a shorter face, higher and broader calvaria. Some of T1KO mice exhibited severe facial developmental defect, such as eye defects and cleft lip and palate, causing embryonic lethality. At the postnatal stages, T1KO mice with severely reduced CS amounts showed malocclusion, general skeletal dysplasia and skin hyperextension, closely resembling Ehlers-Danlos syndrome-like connective tissue disorders. The production of collagen type 1 was significantly downregulated in T1KO mice, and the deposition of CS-binding molecules, Wnt3a, was decreased with CS in extracellular matrices. The collagen fibers were irregular and aggregated, and connective tissues were dysorganized in the skin and calvaria of T1KO mice. These results suggest that CS regulates the shape of the craniofacial skeleton by modulating connective tissue organization and that the remarkable reduction of CS induces hypoplasia of intramembranous ossification and cartilage anomaly, resulting in skeletal dysplasia.
硫酸软骨素（CS）蛋白聚糖是细胞外基质的主要成分，在器官发生中起着重要作用。为了阐明 CS 对颅面发育的作用，我们分析了 CS-N-乙酰半乳糖胺基转移酶-1（T1）基因敲除（KO）小鼠的颅面形态。T1KO 小鼠表现出颅骨内骨化受损，成年小鼠的最终颅骨形状包括脸变短、颅骨变高变宽。一些 T1KO 小鼠表现出严重的面部发育缺陷，如眼睛缺陷和唇腭裂，导致胚胎致死。在出生后的阶段，CS 含量严重减少的 T1KO 小鼠表现出咬合不正、骨骼整体发育不良和皮肤过度伸展，与埃勒斯-当洛斯综合征样结缔组织疾病非常相似。T1KO 小鼠中胶原 1 的产生显著下调，CS 结合分子 Wnt3a 的沉积随细胞外基质中的 CS 减少而减少。T1KO 小鼠的胶原纤维不规则且聚集，皮肤和颅骨中的结缔组织排列紊乱。这些结果表明 CS 通过调节结缔组织组织来调节颅面骨骼的形状，而 CS 的显著减少会导致膜内成骨和软骨异常的发育不良，从而导致骨骼发育不良。
