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

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

doi:10.1038/s41467-025-64361-7

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.

Authors

Jinlong Suo^#¹, Duo Wang^#², Jinghui Wang², Xubin Yin², Xuye Hu², Rui Shao³, Shuqin Chen⁴, Shaokun Sun², Jingyi Feng², Lijun Wang⁴, Heng Feng², Zhengda Li⁵, Wulei Hou⁵, Lei Zhang⁶, Yong Chen², Xianyou Zheng⁷, Zuoyun Wang⁸, 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. suojinlong2015@sibcb.ac.cn.
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. zhengxianyou@126.com.
⁸ Department of Anatomy and Histoembrvology, School of Basic Medical Sciences and Shanghai Pudong Hospital, Pudong Medical Center, Fudan University, Shanghai, China. wangzuoyun@fudan.edu.cn.
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. zouwg94@sibcb.ac.cn.
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. zouwg94@sibcb.ac.cn.
¹¹ Hainan Institute of Regenerative Orthopedics and Sports Medicine, Hainan Academy of Medical Sciences, Hainan Medical University, Hainan, China. zouwg94@sibcb.ac.cn.

^# Contributed equally.

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; Vgll4^fl/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.

MeSH terms

Animals
Cartilage, Articular / metabolism
Cartilage, Articular / pathology
Chondrocytes / metabolism
Collagen / metabolism
DNA-Binding Proteins* / genetics
DNA-Binding Proteins* / metabolism
Disease Models, Animal
Extracellular Matrix* / metabolism
Homeostasis
Humans
Male
Mice
Mice, Knockout
Osteoarthritis* / genetics
Osteoarthritis* / metabolism
Osteoarthritis* / pathology
Osteoarthritis* / therapy
Smad3 Protein / genetics
Smad3 Protein / metabolism
Transcription Factors* / genetics
Transcription Factors* / metabolism

Substances

Smad3 Protein
Transcription Factors
DNA-Binding Proteins
Smad3 protein, mouse
Collagen