PUBLICATION
Identification of Fibroblast Activation Protein as an Osteogenic Suppressor and Anti-osteoporosis Drug Target
- Authors
- Wei, H., Xu, Y., Wang, Y., Xu, L., Mo, C., Li, L., Shen, B., Sun, Y., Cheng, P., Yang, L., Pang, Y., Qin, A., Cao, Y., Morrison, S.J., Yue, R.
- ID
- ZDB-PUB-201020-7
- Date
- 2020
- Source
- Cell Reports 33: 108252 (Journal)
- Registered Authors
- Keywords
- Clec11a, Fap, bone formation, bone resorption, mineralization, osteogenesis, osteolectin, osteoporosis, zebrafish
- MeSH Terms
-
- Aging/metabolism
- Aging/pathology
- Animals
- Bone Resorption/complications
- Bone Resorption/diagnostic imaging
- Bone Resorption/pathology
- Calcification, Physiologic
- Cell Differentiation
- Endopeptidases/metabolism*
- Epistasis, Genetic
- Gene Deletion
- HEK293 Cells
- Hematopoietic Cell Growth Factors/metabolism
- Humans
- Lectins, C-Type/metabolism
- Membrane Proteins/antagonists & inhibitors
- Membrane Proteins/metabolism*
- Mice, Inbred C57BL
- Molecular Targeted Therapy*
- Osteoblasts/metabolism
- Osteoblasts/pathology
- Osteoclasts/metabolism
- Osteoclasts/pathology
- Osteogenesis*
- Osteoporosis/complications
- Osteoporosis/diagnostic imaging
- Osteoporosis/drug therapy*
- Osteoporosis/pathology
- Ovariectomy
- Peptide Hydrolases/metabolism
- Protein Binding
- Zebrafish
- Zebrafish Proteins/metabolism
- PubMed
- 33053358 Full text @ Cell Rep.
Citation
Wei, H., Xu, Y., Wang, Y., Xu, L., Mo, C., Li, L., Shen, B., Sun, Y., Cheng, P., Yang, L., Pang, Y., Qin, A., Cao, Y., Morrison, S.J., Yue, R. (2020) Identification of Fibroblast Activation Protein as an Osteogenic Suppressor and Anti-osteoporosis Drug Target. Cell Reports. 33:108252.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping