Fibroblast activation protein-α interacts with CXCL12 to inactivate canonical Wnt signaling and regulate osteoblast differentiation.

Fibroblast activation protein-α (FAP) has been identified as an osteogenic suppressor and a potential drug target to treat osteoporosis. However, the direct role of FAP in osteoblast differentiation and the mechanism by which FAP works remains to be explored. In the current study we showed that FAP expression increased significantly during osteogenic and adipogenic differentiation of mesenchymal progenitor cells. Functional experiments revealed that FAP suppressed osteoblast differentiation and forced adipocyte formation from mesenchymal progenitor cells. Mechanistic exploration showed that FAP reduced the protein level of C-X-C motif chemokine ligand 12 (CXCL12) through directly degrading the latter. Consistently, the point mutation of the catalytic site rendered FAP fail to reduce CXCL12 protein level and fail to impact osteoblast and adipocyte differentiation. While CXCL12 activated canonical Wnt pathway, FAP inactivated canonical Wnt signaling to regulate differentiation of osteoblasts and adipocytes. CXCL12 was able to promote osteoblast differentiation while suppressing adipocyte differentiation, and attenuated the dysregulation of the differentiation tendencies induced by FAP. Taken as a whole, our study has demonstrated that FAP directly cleaves CXCL12 to inactivate canonical Wnt signaling, and therefore plays a direct role in regulating osteogenic and adipogenic differentiation of mesenchymal progenitor cells.