title: CXCR4 antagonism attenuates load-induced periosteal bone formation in mice.
abstract: Mechanical loading is a key anabolic regulator of bone mass. Stromal cell-derived factor-1 (SDF-1) is a stem cell homing factor that is important in hematopoiesis, angiogenesis, and fracture healing, though its involvement in skeletal mechanoadaptation is virtually unknown. The objective of this study was to characterize skeletal expression patterns of SDF-1 and CXCR4, the receptor for SDF-1, and to determine the role of SDF-1 signaling in load-induced periosteal bone formation. Sixteen-week-old C57BL/6 mice were treated with PBS or AMD3100, an antagonist against CXCR4, and exposed to in vivo ulnar loading (2.8 N peak-to-peak, 2 Hz, 120 cycles). SDF-1 was expressed in cortical and trabecular osteocytes and marrow cells, and CXCR4 was primarily expressed in marrow cells. SDF-1 and CXCR4 expression was enhanced in response to mechanical stimulation. The CXCR4 receptor antagonist AMD3100 significantly attenuated load-induced bone formation and led to smaller adaptive changes in cortical geometric properties as determined by histomorphometric analysis. Our data suggest that SDF-1/CXCR4 signaling plays a critical role in skeletal mechanoadaptation, and may represent a unique therapeutic target for prevention and treatment of age-related and disuse bone loss.
authors.affiliation: Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, California.
authors.forename: Philipp
authors.initials: P
authors.lastname: Leucht
authors.forename: Sara
authors.initials: S
authors.lastname: Temiyasathit
authors.forename: Ashley
authors.initials: A
authors.lastname: Russell
authors.forename: Juan F
authors.initials: JF
authors.lastname: Arguello
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Jacobs
authors.forename: Jill A
authors.initials: JA
authors.lastname: Helms
authors.forename: Alesha B
authors.initials: AB
authors.lastname: Castillo
mesh_terms: D000818:Animals; D001596:Benzylamines; D002454:Cell Differentiation; D054377:Chemokine CXCL12 / Q000235:genetics / Q000502:physiology*; D000080027:Cyclams; D006571:Heterocyclic Compounds / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D010012:Osteogenesis; D012333:RNA, Messenger / Q000032:analysis; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D001596:Benzylamines; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D012333:RNA, Messenger; D019718:Receptors, CXCR4; C088327:plerixafor
keywords: CXCR4; SDF-1; mechanoadaptation; osteogenesis; ulnar loading