WHIM Syndrome-linked CXCR4 mutations drive osteoporosis

Adrienne Anginot, Julie Nguyen, Zeina Abou Nader, Vincent Rondeau, Amélie Bonaud, Maria Kalogeraki, Antoine Boutin, Julia P. Lemos, Valeria Bisio, Joyce Koenen, Lea Hanna Doumit Sakr, Amandine Picart, Amélie Coudert, Sylvain Provot, Nicolas Dulphy, Michel Aurrand-Lions, Stéphane J. C. Mancini, Gwendal Lazennec, David H. McDermott, Fabien Guidez, Claudine Blin-Wakkach, Philip M. Murphy, Martine Cohen-Solal, Marion Espéli, Matthieu Rouleau and Karl Balabanian ()
Additional contact information
Adrienne Anginot: Université Paris Cité, Institut de Recherche Saint-Louis
Julie Nguyen: CNRS, GDR3697 “Microenvironment of tumor niches”
Zeina Abou Nader: Université Paris Cité, Institut de Recherche Saint-Louis
Vincent Rondeau: Université Paris Cité, Institut de Recherche Saint-Louis
Amélie Bonaud: Université Paris Cité, Institut de Recherche Saint-Louis
Maria Kalogeraki: Université Paris Cité, Institut de Recherche Saint-Louis
Antoine Boutin: Université Côte d’Azur, CNRS
Julia P. Lemos: Université Paris Cité, Institut de Recherche Saint-Louis
Valeria Bisio: Université Paris Cité, Institut de Recherche Saint-Louis
Joyce Koenen: CNRS, GDR3697 “Microenvironment of tumor niches”
Lea Hanna Doumit Sakr: AP-HP Hospital Lariboisière
Amandine Picart: AP-HP Hospital Lariboisière
Amélie Coudert: AP-HP Hospital Lariboisière
Sylvain Provot: AP-HP Hospital Lariboisière
Nicolas Dulphy: Université Paris Cité, Institut de Recherche Saint-Louis
Michel Aurrand-Lions: CNRS, GDR3697 “Microenvironment of tumor niches”
Stéphane J. C. Mancini: CNRS, GDR3697 “Microenvironment of tumor niches”
Gwendal Lazennec: CNRS, GDR3697 “Microenvironment of tumor niches”
David H. McDermott: National Institute of Allergy and Infectious Diseases, NIH
Fabien Guidez: The Organization for Partnerships in Leukemia, Hôpital Saint-Louis
Claudine Blin-Wakkach: Université Côte d’Azur, CNRS
Philip M. Murphy: National Institute of Allergy and Infectious Diseases, NIH
Martine Cohen-Solal: AP-HP Hospital Lariboisière
Marion Espéli: Université Paris Cité, Institut de Recherche Saint-Louis
Matthieu Rouleau: Université Côte d’Azur, CNRS
Karl Balabanian: Université Paris Cité, Institut de Recherche Saint-Louis

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract WHIM Syndrome is a rare immunodeficiency caused by gain-of-function CXCR4 mutations. Here we report a decrease in bone mineral density in 25% of WHIM patients and bone defects leading to osteoporosis in a WHIM mouse model. Imbalanced bone tissue is observed in mutant mice combining reduced osteoprogenitor cells and increased osteoclast numbers. Mechanistically, impaired CXCR4 desensitization disrupts cell cycle progression and osteogenic commitment of skeletal stromal/stem cells, while increasing their pro-osteoclastogenic capacities. Impaired osteogenic differentiation is evidenced in primary bone marrow stromal cells from WHIM patients. In mice, chronic treatment with the CXCR4 antagonist AMD3100 normalizes in vitro osteogenic fate of mutant skeletal stromal/stem cells and reverses in vivo the loss of skeletal cells, demonstrating that proper CXCR4 desensitization is required for the osteogenic specification of skeletal stromal/stem cells. Our study provides mechanistic insights into how CXCR4 signaling regulates the osteogenic fate of skeletal cells and the balance between bone formation and resorption.

Date: 2023
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DOI: 10.1038/s41467-023-37791-4

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