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Original Article | Open Access

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

Aoyuan Fan1,, Genbin Wu2,, Jianfang Wang3, Laiya Lu1, Jingyi Wang1, Hanjing Wei3, Yuxi Sun4, Yanhua Xu3,4, Chunyang Mo3, Xiaoying Zhang3, Zhiying Pang1, Zhangyi Pan1, Yiming Wang1, Liangyu Lu1, Guojian Fu2, Mengqiu Ma4, Qiaoling Zhu3, Dandan Cao3, Jiachen Qin3, Feng Yin1,5,6( ), Rui Yue3,5 ( )
Department of Joint Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200092, China
Department of Orthopedic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, China
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
Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, China
Shanghai Clinical Research Center for Aging and Medicine, Shanghai 200040, China

These authors contributed equally: Aoyuan Fan, Genbin Wu

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Abstract

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.

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Bone Research
Volume 11,
December 2023
Article number: 3
DOI: 10.1038/s41413-022-00243-8
Cite this article:
Fan A, Wu G, Wang J, et al. Inhibition of fibroblast activation protein ameliorates cartilage matrix degradation and osteoarthritis progression. Bone Research, 2023, 11: 3. https://doi.org/10.1038/s41413-022-00243-8

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Received: 19 January 2022
Revised: 14 October 2022
Accepted: 11 November 2022
Published: 02 January 2023
© The Author(s) 2023

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