Idiopathic pulmonary fibrosis (IPF) represents a severe and progressive manifestation of idiopathic interstitial pneumonia marked by an uncertain etiology along with an unfavorable prognosis. Osteoglycin (OGN), belonging to the small leucine-rich proteoglycans family, assumes pivotal functions in both tissue formation and damage response. However, the roles and potential mechanisms of OGN in the context of lung fibrosis remain unexplored. The assessment of OGN expression levels in fibrotic lungs was conducted across various experimental lung fibrosis mouse models. To elucidate the effects of OGN on the differentiation of lung myofibroblasts, both OGN knockdown and OGN overexpression were employed in vitro. The expression of integrin αv, along with its colocalization with lysosomes and latency-associated peptide (LAP), was monitored in OGN-knockdown lung myofibroblasts. Furthermore, the role of OGN in lung fibrosis was investigated through OGN knockdown utilizing adeno-related virus serotype 6 (AAV6)-mediated delivery. OGN exhibited upregulation in both lungs and myofibroblasts across diverse lung fibrosis mouse models. And laboratory experiments in vitro demonstrated that OGN knockdown inhibited the TGF-β/Smad signaling pathway in lung myofibroblasts. Conversely, OGN overexpression promoted TGF-β/Smad pathway in these cells. Mechanistic insights revealed that OGN knockdown facilitated lysosome-mediated degradation of integrin αv while inhibiting its binding to latency-associated peptide (LAP). Remarkably, AAV6-targeted OGN knockdown ameliorated the extent of lung fibrosis in experimental mouse models. Our results indicate that inhibiting OGN signaling could serve as a promising therapeutic way for lung fibrosis.

中文翻译：

---

抑制肺肌成纤维细胞中的 OGN 可通过抑制整合素 αv 介导的 TGF-β/Smad 通路激活来减轻肺纤维化


特发性肺纤维化（IPF）是特发性间质性肺炎的一种严重的进行性表现，其特点是病因不明且预后不良。骨甘氨酸（OGN）属于富含亮氨酸的小蛋白聚糖家族，在组织形成和损伤反应中发挥着关键作用。然而，OGN 在肺纤维化中的作用和潜在机制仍有待探索。在各种实验性肺纤维化小鼠模型中对纤维化肺中 OGN 表达水平进行了评估。为了阐明 OGN 对肺肌成纤维细胞分化的影响，体外采用了 OGN 敲低和 OGN 过表达。在 OGN 敲低的肺肌成纤维细胞中监测整合素 αv 的表达及其与溶酶体和潜伏相关肽 (LAP) 的共定位。此外，通过利用腺相关病毒血清型 6 (AAV6) 介导的递送来敲低 OGN，研究了 OGN 在肺纤维化中的作用。在不同的肺纤维化小鼠模型中，OGN 在肺和肌成纤维细胞中均表现出上调。体外实验室实验表明，OGN 敲低可抑制肺肌成纤维细胞中的 TGF-β/Smad 信号通路。相反，OGN 过表达促进了这些细胞中的 TGF-β/Smad 通路。机制研究表明，OGN 敲低促进了溶酶体介导的整合素 αv 降解，同时抑制其与潜伏相关肽 (LAP) 的结合。值得注意的是，AAV6 靶向 OGN 敲低改善了实验小鼠模型中的肺纤维化程度。我们的结果表明，抑制 OGN 信号传导可以作为肺纤维化的一种有前途的治疗方法。