CXCR4 antagonism attenuates load-induced periosteal bone formation in mice

Authors

  • Philipp Leucht,

    1. Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, California
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  • Sara Temiyasathit,

    1. Rehabilitation R&D Center for Tissue Regeneration, Repair, and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, California
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  • Ashley Russell,

    1. Rehabilitation R&D Center for Tissue Regeneration, Repair, and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, California
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  • Juan F. Arguello,

    1. Rehabilitation R&D Center for Tissue Regeneration, Repair, and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, California
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  • Christopher R. Jacobs,

    1. Department of Biomedical Engineering, Columbia University, New York, New York
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  • Jill A. Helms,

    1. Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California
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  • Alesha B. Castillo

    Corresponding author
    1. Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California
    • Rehabilitation R&D Center for Tissue Regeneration, Repair, and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, California
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  • The authors have no conflicts of interest.

Correspondence to: Alesha B. Castillo (T: 650-493-5000 ext. 66252; F: 650-493-4919; E-mail: alesha.castillo@stanford.edu)

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. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:1828–1838, 2013

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