Targeting VGLL4 maintains extracellular matrix homeostasis and mitigates osteoarthritis in a preclinical model
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<sup>fl/fl</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.
Authors
- Jinlong Suo (ORCID: https://orcid.org/0000-0003-3389-3776)
- Xianyou Zheng (ORCID: https://orcid.org/0000-0002-9770-5394)
- Xuye Hu
- Weiguo Zou (ORCID: https://orcid.org/0000-0003-2516-0302)
- Heng Feng (ORCID: https://orcid.org/0000-0001-6830-4607)
- Xubin Yin
- Shuqin Chen (ORCID: https://orcid.org/0000-0002-8260-5809)
- Wulei Hou
- Zuoyun Wang (ORCID: https://orcid.org/0000-0003-4428-5477)
- Jingyi Feng (ORCID: https://orcid.org/0000-0001-5064-7484)
- Lijun Wang (ORCID: https://orcid.org/0000-0002-3686-6098)
- Zhen Li (ORCID: https://orcid.org/0000-0002-2335-3744)
- Lei Zhang (ORCID: https://orcid.org/0000-0003-2566-6493)
- Rui Shao (ORCID: https://orcid.org/0000-0002-7388-851X)
- Duo Wang (ORCID: https://orcid.org/0000-0001-9363-7796)
- Shaokun Sun (ORCID: https://orcid.org/0000-0003-3896-6751)
- Yong Chen (ORCID: https://orcid.org/0000-0001-5857-6086)
- Jinghui Wang (ORCID: https://orcid.org/0000-0002-4999-2106)
Institutions
- Shanghai Jiao Tong University (CN)
- Hainan Provincial Academy of Agricultural Sciences (CN)
- Center for Excellence in Molecular Cell Science (CN)
- Pudong Medical Center (CN)
- Shanghai Sixth People's Hospital (CN)
- Hainan Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-22
- DOI
- https://doi.org/10.1038/s41467-025-64361-7
- Citations
- 2
- Primary Topic
- Cell Adhesion Molecules Research
- Type
- article
- Field-Weighted Citation Impact
- 3.24
Funders
- Sanofi
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Science and Technology Commission of Shanghai Municipality
- Shanghai Jiao Tong University
- National Key Research and Development Program of China