2. Academic Validation
  3. Targeting VGLL4 maintains extracellular matrix homeostasis and mitigates osteoarthritis in a preclinical model

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

  • Nat Commun. 2025 Oct 22;16(1):9325. doi: 10.1038/s41467-025-64361-7.
Jinlong Suo # 1,  Duo Wang # 2,  Jinghui Wang 2,  Xubin Yin 2,  Xuye Hu 2,  Rui Shao 3,  Shuqin Chen 4,  Shaokun Sun 2,  Jingyi Feng 2,  Lijun Wang 4,  Heng Feng 2,  Zhengda Li 5,  Wulei Hou 5,  Lei Zhang 6,  Yong Chen 2,  Xianyou Zheng 7,  Zuoyun Wang 8,  Weiguo Zou 9 10 11
Affiliations

Affiliations

  • 1 Institute of Microsurgery on Extremities, Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 2 CAS Center for Excellence in Molecular Cell Sciences, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
  • 3 Institute of Microsurgery on Extremities, Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 Hainan Institute of Regenerative Orthopedics and Sports Medicine, Hainan Academy of Medical Sciences, Hainan Medical University, Hainan, China.
  • 5 Department of Anatomy and Histoembrvology, School of Basic Medical Sciences and Shanghai Pudong Hospital, Pudong Medical Center, Fudan University, Shanghai, China.
  • 6 School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
  • 7 Institute of Microsurgery on Extremities, Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 8 Department of Anatomy and Histoembrvology, School of Basic Medical Sciences and Shanghai Pudong Hospital, Pudong Medical Center, Fudan University, Shanghai, China. [email protected].
  • 9 Institute of Microsurgery on Extremities, Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 10 CAS Center for Excellence in Molecular Cell Sciences, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 11 Hainan Institute of Regenerative Orthopedics and Sports Medicine, Hainan Academy of Medical Sciences, Hainan Medical University, Hainan, China. [email protected].
  • # Contributed equally.
PMID: 41125571 DOI: 10.1038/s41467-025-64361-7
Abstract

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.

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