Research Paper Volume 13, Issue 24 pp 25717—25728

Calcification in Werner syndrome associated with lymphatic vessels aging

Hideyuki Ogata1, , Shinsuke Akita1, , Sanae Ikehara2,3, , Kazuhiko Azuma3, , Takashi Yamaguchi3, , Maihulan Maimaiti2, , Yoshiro Maezawa4,5, , Yoshitaka Kubota1, , Koutaro Yokote4,5, , Nobuyuki Mitsukawa1, , Yuzuru Ikehara2,3, ,

  • 1 Department of Plastic, Reconstructive, and Aesthetic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
  • 2 Department of Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan
  • 3 Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan
  • 4 Department of Endocrinology, Hematology and Gerontology, Graduate School of Medicine, Chiba University, Chiba, Japan
  • 5 Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, Chiba, Japan

Received: June 7, 2021       Accepted: December 10, 2021       Published: December 27, 2021
How to Cite

Copyright: © 2021 Ogata et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


In addition to the symptoms of aging, the main symptoms in Werner syndrome (WS), a hereditary premature aging disease, include calcification of subcutaneous tissue with solid pain and refractory skin ulcers. However, the mechanism of calcification in WS remains unclear. In this study, the histological analysis of the skin around the ulcer with calcification revealed an accumulation of calcium phosphate in the lymphatic vessels. Moreover, the morphological comparison with the lymphatic vessels in PAD patients with chronic skin ulcers demonstrated the ongoing lymphatic remodeling in WS patients because of the narrow luminal cross-sectional area (LA) of the lymphatic vessels but the increment of lymphatic microvessels density (MLVD). Additionally, fluorescence immunohistochemical analysis presented the cytoplasmic distribution and the accumulation of WRN proteins in endothelial cells on remodeling lymphatic vessels. In summary, these results point out a relationship between calcification in lymphatic vessels and the remodeling of lymphatic vessels and suggest the significance of the accumulation of WRN mutant proteins as an age-related change in WS patients. Thus, cytoplasmic accumulation of WRN protein can be an indicator of the decreasing drainage function of the lymphatic vessels and the increased risk of skin ulcers and calcification in the lymphatic vessels.


WS: Werner syndrome; LA: luminal cross-sectional area; MLVD: lymphatic microvessel density; LECs: lymphatic endothelial cells; PAD: peripheral arterial diseases; ANOVA: analysis of variance; SEM: standard error of the mean.