2. Academic Validation
  3. Targeting Fascin1 maintains chondrocytes phenotype and attenuates osteoarthritis development

Targeting Fascin1 maintains chondrocytes phenotype and attenuates osteoarthritis development

  • Bone Res. 2024 Sep 4;12(1):50. doi: 10.1038/s41413-024-00357-1.
Panpan Yang # 1,  Yun Xiao # 1,  Liangyu Chen # 1,  Chengliang Yang 2,  Qinwei Cheng 1,  Honghao Li 1,  Dalin Chen 1,  Junfeng Wu 1,  Zhengquan Liao 1,  Changsheng Yang 1,  Chong Wang 3,  Hong Wang 1,  Bin Huang 1,  Ee Ke 4,  Xiaochun Bai 5 6,  Kai Li 7
Affiliations

Affiliations

  • 1 Academy of Orthopedics, Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
  • 2 Guangxi Key Laboratory of Basic and Translational Research of Bone and Joint Degenerative Diseases, Guangxi Biomedical Materials Engineering Research Center for Bone and Joint Degenerative Diseases, Department of Orthopedics, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China.
  • 3 School of Mechanical Engineering, Dongguan University of Technology, Dongguan, Guangdong, China.
  • 4 Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangdong Lung Cancer Institute, Guangzhou, China.
  • 5 Academy of Orthopedics, Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China. baixc15@smu.edu.cn.
  • 6 Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China. baixc15@smu.edu.cn.
  • 7 Academy of Orthopedics, Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China. lk516433415@smu.edu.cn.
  • # Contributed equally.
PMID: 39231936 DOI: 10.1038/s41413-024-00357-1
Abstract

Osteoarthritis (OA) is the most common form of arthritic disease, and phenotypic modification of chondrocytes is an important mechanism that contributes to the loss of cartilage homeostasis. This study identified that Fascin actin-bundling protein 1 (FSCN1) plays a pivotal role in regulating chondrocytes phenotype and maintaining cartilage homeostasis. Proteome-wide screening revealed markedly upregulated FSCN1 protein expression in human OA cartilage. FSCN1 accumulation was confirmed in the superficial layer of OA cartilage from humans and mice, primarily in dedifferentiated-like chondrocytes, associated with enhanced actin stress fiber formation and upregulated type I and III collagens. FSCN1-inducible knockout mice exhibited delayed cartilage degeneration following experimental OA surgery. Mechanistically, FSCN1 promoted actin polymerization and disrupted the inhibition of Decorin on TGF-β1, leading to excessive TGF-β1 production and ALK1/Smad1/5 signaling activation, thus, accelerated chondrocyte dedifferentiation. Intra-articular injection of FSCN1-overexpressing adeno-associated virus exacerbated OA progression in mice, which was mitigated by an ALK1 Inhibitor. Moreover, FSCN1 inhibitor NP-G2-044 effectively reduced extracellular matrix degradation in OA mice, cultured human OA chondrocytes, and cartilage explants by suppressing ALK1/Smad1/5 signaling. These findings suggest that targeting FSCN1 represents a promising therapeutic approach for OA.

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