Scholarlink

<p>Geleophysic dysplasia (GD) is a rare genetic disorder characterized by short stature, joint contractures, and cardiopulmonary complications, with early mortality, and linked to mutations in <i>ADAMTSL2</i> (GD1), <i>FBN1</i> (GD2), or <i>LTBP3</i> (GD3) genes. These mutations are hypothesized to disrupt extracellular matrix (ECM) organization and enhance transforming growth factor beta (TGF-β) signaling. Losartan, an angiotensin II receptor blocker, has been proposed to mitigate TGF-β-mediated pathologies. In this study we tested the efficacy of losartan as a therapeutic drug for GD. We evaluated losartan’s therapeutic potential using <i>Adamtsl2</i> p.A165T mutant mice and patient-derived fibroblasts. Survival, growth, TGF-β signaling, and ECM protein expression were assessed. Losartan did not improve survival or growth in our mutant mice. Compared with control fibroblasts, patient-derived fibroblasts showed reduced basal TGF-β1 secretion. Consistent with this finding, transcriptomic analyses did not reveal activation of the TGF-β signaling pathway, and no differences in SMAD phosphorylation were observed between patient and control cells. Losartan treatment failed to modulate TGF-β signaling or ECM protein incorporation. These results suggest limited benefits of losartan in GD and challenge the notion of TGF-β dysregulation in GD pathogenesis, indicating a need for alternative targeted therapies.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Losartan shows limited benefit in preclinical models of Geleophysic dysplasia

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月23日

查看全文
  • Alejo A. Morales,
  • Vladimir Camarena,
  • LéShon Peart,
  • Sarah Smithson,
  • Katherina Walz,
  • Gaofeng Wang,
  • Mustafa Tekin

摘要

Geleophysic dysplasia (GD) is a rare genetic disorder characterized by short stature, joint contractures, and cardiopulmonary complications, with early mortality, and linked to mutations in ADAMTSL2 (GD1), FBN1 (GD2), or LTBP3 (GD3) genes. These mutations are hypothesized to disrupt extracellular matrix (ECM) organization and enhance transforming growth factor beta (TGF-β) signaling. Losartan, an angiotensin II receptor blocker, has been proposed to mitigate TGF-β-mediated pathologies. In this study we tested the efficacy of losartan as a therapeutic drug for GD. We evaluated losartan’s therapeutic potential using Adamtsl2 p.A165T mutant mice and patient-derived fibroblasts. Survival, growth, TGF-β signaling, and ECM protein expression were assessed. Losartan did not improve survival or growth in our mutant mice. Compared with control fibroblasts, patient-derived fibroblasts showed reduced basal TGF-β1 secretion. Consistent with this finding, transcriptomic analyses did not reveal activation of the TGF-β signaling pathway, and no differences in SMAD phosphorylation were observed between patient and control cells. Losartan treatment failed to modulate TGF-β signaling or ECM protein incorporation. These results suggest limited benefits of losartan in GD and challenge the notion of TGF-β dysregulation in GD pathogenesis, indicating a need for alternative targeted therapies.