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

Area of Science:

• Biochemistry
• Molecular Biology
• Orthopedics

Background:

• Osteogenic suppressors regulate bone metabolism and are potential osteoporosis drug targets.
• Limited understanding of osteogenesis mechanisms hinders the identification of druggable suppressors.

Purpose of the Study:

• To identify novel osteogenic suppressors.
• To investigate the role of fibroblast activation protein (Fap) in bone metabolism.
• To evaluate Fap as a potential therapeutic target for osteoporosis.

Main Methods:

• Genetic deletion of Fap in mice.
• Pharmacological inhibition of Fap in mice.
• Analysis of canonical Wnt and nuclear factor κB (NF-κB) pathways.
• Ovariectomized mouse model of osteoporosis.
• Epistasis analyses in zebrafish.

Main Results:

• Genetic deletion of Fap ameliorates age-related bone loss.
• Fap inhibition promotes bone formation and inhibits resorption by regulating Wnt and NF-κB pathways.
• Fap inhibition promotes osteoblast and inhibits osteoclast differentiation, attenuating osteoporosis in mice.
• Osteolectin inhibits Fap to promote zebrafish vertebrae mineralization.

Conclusions:

• Fibroblast activation protein (Fap) is an osteogenic suppressor.
• Fap is a potential drug target for treating osteoporosis.
• Osteolectin acts as an endogenous inhibitor of Fap in bone mineralization.