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Updated: Aug 13, 2025
08:01
Stimulation of Notch Signaling in Mouse Osteoclast Precursors
Published on: February 28, 2017
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DPP4-Truncated CXCL12 Alters CXCR4/ACKR3 Signaling, Osteogenic Cell Differentiation, Migration, and Senescence
Ahmed M Elmansi1,2,3, Nada H Eisa1,2,4, Sudharsan Periyasamy-Thandavan5
1Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29403, United States.
ACS Pharmacology & Translational Science
|January 20, 2023
Summary
Dipeptidyl peptidase 4 (DPP4) cleaves CXCL12, creating CXCL12(3-68). This metabolite inhibits stem cell differentiation and migration, impacting bone health and other CXCL12-related research.
Area of Science:
- Cell Biology
- Biochemistry
- Stem Cell Biology
Background:
- Stromal derived factor-1 (CXCL12) is a cytokine secreted by bone marrow skeletal stem cells (SSCs) that regulates cell functions.
- Dipeptidyl peptidase 4 (DPP4) rapidly cleaves CXCL12, generating metabolites like CXCL12(3-68).
Purpose of the Study:
- To investigate the bioactivity of the DPP4-generated CXCL12 metabolite, CXCL12(3-68).
- To elucidate the molecular mechanisms underlying CXCL12(3-68) activity and its impact on SSCs and osteoclastogenesis.
Main Methods:
- In vitro assays including cell differentiation, migration, and senescence induction.
- High-throughput G-protein-coupled receptor (GPCR) screening (GPCRome) and bioluminescent resonance energy transfer (BRET) assays.
- Reverse phase protein array (RPPA) analysis.
Main Results:
- CXCL12(3-68) inhibited osteogenic differentiation of SSCs and osteoclastogenesis of RAW-264.7 cells.
- CXCL12(3-68) induced senescence in SSCs and diminished their migration.
- CXCL12(3-68) acts as a competitive antagonist to CXCR4 via atypical cytokine receptor 3 and β-arrestin recruitment.
- DPP4-cleaved CXCL12 exhibits a distinct downstream signaling profile.
Conclusions:
- DPP4 proteolysis of CXCL12 generates a metabolite with significant, previously overlooked bioactivity.
- CXCL12(3-68) plays a critical role in regulating stem cell function and bone metabolism.
- Findings offer insights into osteoporosis, fracture repair, and potential clinical implications in various CXCL12-related fields.
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