2. Academic Validation
  3. Identification of Fibroblast Activation Protein as an Osteogenic Suppressor and Anti-osteoporosis Drug Target

Identification of Fibroblast Activation Protein as an Osteogenic Suppressor and Anti-osteoporosis Drug Target

  • Cell Rep. 2020 Oct 13;33(2):108252. doi: 10.1016/j.celrep.2020.108252.
Hanjing Wei 1,  Yanhua Xu 2,  Yibin Wang 1,  Liting Xu 1,  Chunyang Mo 1,  Liangzi Li 1,  Bo Shen 3,  Yao Sun 4,  Pengzhen Cheng 5,  Liu Yang 5,  Yichuan Pang 6,  An Qin 6,  Ying Cao 1,  Sean J Morrison 7,  Rui Yue 8
Affiliations

Affiliations

  • 1 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.
  • 2 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, 1239 Siping Road, Shanghai 200072, China.
  • 3 Department of Pediatrics and Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 4 Department of Implantology, School and Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai 200072, China.
  • 5 Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
  • 6 Department of Orthopedics, Shanghai Key Laboratory of Orthopedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China.
  • 7 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pediatrics and Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 8 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. Electronic address: [email protected].
PMID: 33053358 DOI: 10.1016/j.celrep.2020.108252
Abstract

Osteogenic suppressors such as Sclerostin not only regulate skeletal development and regeneration but also serve as anti-osteoporosis drug targets. However, very few druggable suppressors have been identified due to limited understanding of the molecular mechanisms governing osteogenesis. Here, we show that fibroblast activation protein (FAP), a serine protease inhibited by the bone growth factor Osteolectin, is an osteogenic suppressor. Genetic deletion of FAP significantly ameliorates limb trabecular bone loss during aging. Pharmacological inhibition of FAP significantly promotes bone formation and inhibits bone resorption in wild-type mice by differentially regulating canonical Wnt and nuclear factor κB (NF-κB) pathways. Pharmacological inhibition of FAP promotes osteoblast differentiation, inhibits osteoclast differentiation, and significantly attenuates osteoporosis in ovariectomized mice. Epistasis analyses in zebrafish show that Osteolectin functions as an endogenous inhibitor of FAP to promote vertebrae mineralization. Taken together, we identify FAP as an important osteogenic suppressor and a potential drug target to treat osteoporosis.

Keywords

Clec11a; Fap; bone formation; bone resorption; mineralization; osteogenesis; osteolectin; osteoporosis; zebrafish.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-101801
    ≥98.0%, FAP Inhibitor
    FAP