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<p>Extracellular matrix homeostasis is crucial for hyaline cartilage integrity, however, the mechanism of extracellular matrix homeostasis in hyaline cartilage is poorly understood. Single-cell sequencing shows that VGLL4 is highly expressed in chondrocytes but declines after injury/aging. VGLL4 deficiency impairs collagen/elastin formation, causes extracellular matrix disorganization and osteoarthritis in <i>Col2-CreERT2; Vgll4</i><sup><i>fl/fl</i></sup> mice, and is exacerbated by destabilization of the medial meniscus surgery. Mechanistically, the VGLL4-TEAD-SMAD3 complex maintains extracellular matrix homeostasis through specific interactions: TEAD4 (E263/D266/ Q269/H427) binds SMAD3 (K81/F260) via hydrogen bonds and hydrophobic contacts, while VGLL4 (H240/F241) engages TEAD4 (F337/F373) through π-stacking. Notably, intra-articular delivery of adeno-associated virus encoding either SMAD3 or VGLL4 effectively ameliorates osteoarthritis pathology, whereas interaction-deficient mutants lose therapeutic efficacy. This study demonstrates that VGLL4 serves as a critical regulator of extracellular matrix homeostasis in chondrocytes. The VGLL4 complex represents a potential therapeutic target for treating osteoarthritis and cartilage fibrosis.</p>

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Targeting VGLL4 maintains extracellular matrix homeostasis and mitigates osteoarthritis in a preclinical model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月22日

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  • Jinlong Suo,
  • Duo Wang,
  • Jinghui Wang,
  • Xubin Yin,
  • Xuye Hu,
  • Rui Shao,
  • Shuqin Chen,
  • Shaokun Sun,
  • Jingyi Feng,
  • Lijun Wang,
  • Heng Feng,
  • Zhengda Li,
  • Wulei Hou,
  • Lei Zhang,
  • Yong Chen,
  • Xianyou Zheng,
  • Zuoyun Wang,
  • Weiguo Zou

摘要

Extracellular matrix homeostasis is crucial for hyaline cartilage integrity, however, the mechanism of extracellular matrix homeostasis in hyaline cartilage is poorly understood. Single-cell sequencing shows that VGLL4 is highly expressed in chondrocytes but declines after injury/aging. VGLL4 deficiency impairs collagen/elastin formation, causes extracellular matrix disorganization and osteoarthritis in Col2-CreERT2; Vgll4fl/fl mice, and is exacerbated by destabilization of the medial meniscus surgery. Mechanistically, the VGLL4-TEAD-SMAD3 complex maintains extracellular matrix homeostasis through specific interactions: TEAD4 (E263/D266/ Q269/H427) binds SMAD3 (K81/F260) via hydrogen bonds and hydrophobic contacts, while VGLL4 (H240/F241) engages TEAD4 (F337/F373) through π-stacking. Notably, intra-articular delivery of adeno-associated virus encoding either SMAD3 or VGLL4 effectively ameliorates osteoarthritis pathology, whereas interaction-deficient mutants lose therapeutic efficacy. This study demonstrates that VGLL4 serves as a critical regulator of extracellular matrix homeostasis in chondrocytes. The VGLL4 complex represents a potential therapeutic target for treating osteoarthritis and cartilage fibrosis.