WHIM Syndrome-linked CXCR4 Mutations Drive Osteoporosis

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Apr 12

PMID 37045841

Authors

Adrienne Anginot

Julie Nguyen

Zeina Abou Nader

Vincent Rondeau

Amelie Bonaud

Maria Kalogeraki

Antoine Boutin

Julia P Lemos

Valeria Bisio

Joyce Koenen

Lea Hanna Doumit Sakr

Amandine Picart

Amelie Coudert

Sylvain Provot

Nicolas Dulphy

Michel Aurrand-Lions

Stephane J C Mancini

Gwendal Lazennec

David H McDermott

Fabien Guidez

Claudine Blin-Wakkach

Philip M Murphy

Martine Cohen-Solal

Marion Espeli

Matthieu Rouleau

Karl Balabanian

Affiliations

Soon will be listed here.

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.

Citing Articles

CXCR4 antagonism ameliorates leukocyte abnormalities in a preclinical model of WHIM syndrome.

Roland L, Nguyen C, Zmajkovicova K, Khamyath M, Kalogeraki M, Schell B Front Immunol. 2024; 15:1468823.

PMID: 39588369 PMC: 11586337. DOI: 10.3389/fimmu.2024.1468823.

CXCR4 signaling determines the fate of hematopoietic multipotent progenitors by stimulating mTOR activity and mitochondrial metabolism.

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PMID: 39471249 PMC: 11733996. DOI: 10.1126/scisignal.adl5100.

The complex nature of CXCR4 mutations in WHIM syndrome.

Rodriguez-Frade J, Gonzalez-Granado L, Santiago C, Mellado M Front Immunol. 2024; 15:1406532.

PMID: 39035006 PMC: 11257845. DOI: 10.3389/fimmu.2024.1406532.

Periodontal disease in patients with WHIM syndrome.

Brenchley L, McDermott D, Gardner P, Silva L, Gao J, Cho E J Clin Periodontol. 2024; 51(4):464-473.

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