Sulfatases are determinants of alveolar formation

详细信息	查看全文 | 推荐本文 |

• 作者：Emilio Arteaga-Solis^a ; ^b ; Carmine Settembre^a ; ^c ; Andrea Ballabio^c ; ^d ; Gerard Karsenty^a ; ^{Gk2172@columbia.edu}
• 关键词：Alveolarization ; Sumf1 ; Glycosaminoglycans ; Sulfatases ; TGF尾
• 刊名：Matrix Biology
• 出版年：2012
• 期刊代码：64_0945053x
• 类别：imm
• 出版时间：May, 2012
• 卷：31
• 期：4
• 页码：253-260
• 文件大小：2014 K

摘要

Alveolar formation or alveolarization is orchestrated by a finely regulated and complex interaction between growth factors and extracellular matrix proteins. The lung parenchyma contains various extracellular matrix proteins including proteoglycans, which are composed of glycosaminoglycans (GAGs) linked to a protein core. Although GAGs are known to regulate growth factor distribution and activity according to their degree of sulfation the role of sulfated GAG in the respiratory system is not well understood. The degree of sulfation of GAGs is regulated in part, by sulfatases that remove sulfate groups. In vertebrates, the enzyme Sulfatase-Modifying Factor 1 (Sumf1) activates all sulfatases. Here we utilized mice lacking m>Sumf1m>^{m>鈭?鈭?/em>} to study the importance of proteoglycan desulfation in lung development. The m>Sumf1m>^{m>鈭?鈭?/em>} mice have normal lungs up until the onset of alveolarization at post-natal day 5 (P5). We detected increased deposition of sulfated GAG throughout the lung parenchyma and a decrease in alveolar septa formation. Moreover, stereological analysis showed that the alveolar volume is 20%larger in m>Sumf1m>^{m>鈭?鈭?/em>} as compared to wild type (WT) mice at P10 and P30. Additionally, pulmonary function test was consistent with increased alveolar volume. Genetic experiments demonstrate that in m>Sumf1m>^{m>鈭?鈭?/em>} mice arrest of alveolarization is independent of fibroblast growth factor signaling. In turn, the m>Sumf1m>^{m>鈭?鈭?/em>} mice have increased transforming growth factor 尾 (TGF尾) signaling and m>in vivom> injection of TGF尾 neutralizing antibody leads to normalization of alveolarization. Thus, absence of sulfatase activity increases sulfated GAG deposition in the lungs causing deregulation of TGF尾 signaling and arrest of alveolarization.