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Fibroblast activation protein-α interacts with CXCL12 to inactivate canonical Wnt signaling and regulate osteoblast
Yuan Dong1, Xingli Hu1, Wei Liu2
1NHC Key Lab of Hormones and Development, Tianjin Key Lab of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, People's Republic of China.
Abstract:
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.
Insights
Fibroblast activation protein-α (FAP) degrades CXCL12, inhibiting Wnt signaling and suppressing osteoblast differentiation. This reveals FAP
Area of Science:
- Cell Biology
- Biochemistry
- Bone Biology
Background:
- Fibroblast activation protein-α (FAP) is implicated as an osteogenic suppressor and a potential therapeutic target for osteoporosis.
- The precise function of FAP in osteoblast differentiation and its underlying mechanisms require further investigation.
Purpose of the Study:
- To elucidate the direct role of FAP in osteoblast and adipocyte differentiation of mesenchymal progenitor cells.
- To uncover the molecular mechanism by which FAP regulates these differentiation processes.
Main Methods:
- Quantification of FAP expression during osteogenic and adipogenic differentiation.
- Functional assays to assess the impact of FAP on cell differentiation.
- Mechanistic studies involving protein degradation assays and Wnt pathway analysis.
- Site-directed mutagenesis to evaluate the enzymatic activity of FAP.
Main Results:
- FAP expression significantly increased during osteogenic and adipogenic differentiation.
- FAP suppressed osteoblast differentiation and promoted adipocyte formation.
- FAP directly degraded C-X-C motif chemokine ligand 12 (CXCL12), reducing its protein levels.
- Catalytic inactivation of FAP abolished its effects on CXCL12 levels and cell differentiation.
- FAP inactivated the canonical Wnt pathway, while CXCL12 activated it.
- CXCL12 counteracted FAP-induced differentiation alterations.
Conclusions:
- FAP directly cleaves CXCL12, leading to the inactivation of the canonical Wnt signaling pathway.
- FAP plays a direct role in regulating both osteogenic and adipogenic differentiation of mesenchymal progenitor cells.
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