Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA; Bio-Rad Laboratories, Hercules, California, USA.
Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA; Institute of Enzymology, Research Center for Natural Sciences, Hungarian Academy of Sciences Centre of Excellence, Budapest, Hungary.
J Invest Dermatol. 2024 Aug;144(8):1772-1783.e3. doi: 10.1016/j.jid.2024.01.026. Epub 2024 Feb 15.
Physiological calcification of soft tissues is a common occurrence in aging and various acquired and inherited disorders. ABCC6 sequence variations cause the calcification phenotype of pseudoxanthoma elasticum (PXE) as well as some cases of generalized arterial calcification of infancy, which is otherwise caused by defective ENPP1. ABCC6 is primarily expressed in the liver, which has given the impression that the liver is central to the pathophysiology of PXE/generalized arterial calcification of infancy. The emergence of inflammation as a contributor to the calcification in PXE suggested that peripheral tissues play a larger role than expected. In this study, we investigated whether bone marrow-derived ABCC6 contributes to the calcification in PXE. In Abcc6 mice, we observed prevalent mineralization in several lymph nodes and surrounding connective tissues and an extensive network of lymphatic vessels within vibrissae, a calcified tissue in Abcc6 mice. Furthermore, we found evidence of lymphangiogenesis in patients with PXE and mouse skin, suggesting an inflammatory process. Finally, restoring wild-type bone marrow in Abcc6 mice produced a significant reduction of calcification, suggesting that the liver alone is not sufficient to fully inhibit mineralization. With evidence that ABCC6 is expressed in lymphocytes, we suggest that the adaptative immune system and inflammation largely contribute to the calcification in PXE/generalized arterial calcification of infancy.
软组织的生理钙化是衰老和各种获得性及遗传性疾病的常见现象。ABCC6 序列变异导致弹性假黄瘤（PXE）的钙化表型以及一些婴儿全身性动脉钙化的病例，而后者是由 ENPP1 缺陷引起的。ABCC6 主要在肝脏中表达，这给人一种印象，即肝脏是 PXE/婴儿全身性动脉钙化发病机制的核心。炎症作为 PXE 钙化的一个促成因素的出现表明，外周组织的作用比预期的更大。在这项研究中，我们研究了骨髓来源的 ABCC6 是否有助于 PXE 的钙化。在 Abcc6 小鼠中，我们观察到几个淋巴结及其周围结缔组织以及触须内广泛的淋巴管网络普遍存在矿化，触须是 Abcc6 小鼠中的一种钙化组织。此外，我们在 PXE 患者和小鼠皮肤中发现了淋巴管生成的证据，表明存在炎症过程。最后，在 Abcc6 小鼠中恢复野生型骨髓产生了显著减少的钙化，表明仅肝脏不足以完全抑制矿化。有证据表明 ABCC6 在淋巴细胞中表达，我们推测适应性免疫系统和炎症在很大程度上导致了 PXE/婴儿全身性动脉钙化的钙化。
