Inhibition of fibroblast activation protein ameliorates cartilage matrix degradation and osteoarthritis progression.

Jan 02, 2023

Experts: Aoyuan Fan,Genbin Wu,Jianfang Wang,Laiya Lu,Jingyi Wang,Hanjing Wei,Yuxi Sun,Yanhua Xu,Chunyang Mo,Xiaoying Zhang,Zhiying Pang,Zhangyi Pan,Yiming Wang,Liangyu Lu,Guojian Fu,Mengqiu Ma,Qiaoling Zhu,Dandan Cao,Jiachen Qin,Feng Yin,Rui Yue

Fibroblast activation protein (Fap) is a serine protease that degrades denatured type I collagen, α2-antiplasmin and FGF21. Fap is highly expressed in bone marrow stromal cells and functions as an osteogenic suppressor and can be inhibited by the bone growth factor Osteolectin (Oln). Fap is also expressed in synovial fibroblasts and positively correlated with the severity of rheumatoid arthritis (RA). However, whether Fap plays a critical role in osteoarthritis (OA) remains poorly understood. Here, we found that Fap is significantly elevated in osteoarthritic synovium, while the genetic deletion or pharmacological inhibition of Fap significantly ameliorated posttraumatic OA in mice. Mechanistically, we found that Fap degrades denatured type II collagen (Col II) and Mmp13-cleaved native Col II. Intra-articular injection of rFap significantly accelerated Col II degradation and OA progression. In contrast, Oln is expressed in the superficial layer of articular cartilage and is significantly downregulated in OA. Genetic deletion of Oln significantly exacerbated OA progression, which was partially rescued by Fap deletion or inhibition. Intra-articular injection of rOln significantly ameliorated OA progression. Taken together, these findings identify Fap as a critical pathogenic factor in OA that could be targeted by both synthetic and endogenous inhibitors to ameliorate articular cartilage degradation.
© 2023. The Author(s).

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ABOUT THE EXPERTS

Aoyuan Fan,Genbin Wu,Jianfang Wang,Laiya Lu,Jingyi Wang,Hanjing Wei,Yuxi Sun,Yanhua Xu,Chunyang Mo,Xiaoying Zhang,Zhiying Pang,Zhangyi Pan,Yiming Wang,Liangyu Lu,Guojian Fu,Mengqiu Ma,Qiaoling Zhu,Dandan Cao,Jiachen Qin,Feng Yin,Rui Yue

Aoyuan Fan

Department of Joint Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200092, China.

Genbin Wu

Department of Orthopedic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200240, China.

Jianfang Wang

Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.

Laiya Lu

Department of Joint Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200092, China.

Jingyi Wang

Department of Joint Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200092, China.

Hanjing Wei

Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.

Yuxi Sun

Department of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, China.

Yanhua Xu

Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.

Department of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, China.

Chunyang Mo

Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.

Xiaoying Zhang

Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.

Zhiying Pang

Department of Joint Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200092, China.

Zhangyi Pan

Department of Joint Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200092, China.

Yiming Wang

Department of Joint Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200092, China.

Liangyu Lu

Department of Joint Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200092, China.

Guojian Fu

Department of Orthopedic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200240, China.

Mengqiu Ma

Department of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, China.

Qiaoling Zhu

Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.

Dandan Cao

Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.

Jiachen Qin

Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.

Feng Yin

Department of Joint Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200092, China. 001yinfeng@sina.com.

Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China. 001yinfeng@sina.com.

Shanghai Clinical Research Center for Aging and Medicine, Shanghai, 200040, China. 001yinfeng@sina.com.

Rui Yue

Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China. ryue@tongji.edu.cn.

Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China. ryue@tongji.edu.cn.