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
  • 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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