WHIM Syndrome-linked CXCR4 mutations drive osteoporosis
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...
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-37791-4 |
| _version_ | 1797845877344174080 |
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| author | 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 Karl Balabanian |
| author_facet | 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 Karl Balabanian |
| author_sort | Adrienne Anginot |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T17:46:05Z |
| format | Article |
| id | doaj.art-71e743108c284ff4a7d508b10f487735 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-09T17:46:05Z |
| publishDate | 2023-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-71e743108c284ff4a7d508b10f4877352023-04-16T11:19:15ZengNature PortfolioNature Communications2041-17232023-04-0114112010.1038/s41467-023-37791-4WHIM Syndrome-linked CXCR4 mutations drive osteoporosisAdrienne Anginot0Julie Nguyen1Zeina Abou Nader2Vincent Rondeau3Amélie Bonaud4Maria Kalogeraki5Antoine Boutin6Julia P. Lemos7Valeria Bisio8Joyce Koenen9Lea Hanna Doumit Sakr10Amandine Picart11Amélie Coudert12Sylvain Provot13Nicolas Dulphy14Michel Aurrand-Lions15Stéphane J. C. Mancini16Gwendal Lazennec17David H. McDermott18Fabien Guidez19Claudine Blin-Wakkach20Philip M. Murphy21Martine Cohen-Solal22Marion Espéli23Matthieu Rouleau24Karl Balabanian25Université Paris Cité, Institut de Recherche Saint-LouisCNRS, GDR3697 “Microenvironment of tumor niches”Université Paris Cité, Institut de Recherche Saint-LouisUniversité Paris Cité, Institut de Recherche Saint-LouisUniversité Paris Cité, Institut de Recherche Saint-LouisUniversité Paris Cité, Institut de Recherche Saint-LouisUniversité Côte d’Azur, CNRSUniversité Paris Cité, Institut de Recherche Saint-LouisUniversité Paris Cité, Institut de Recherche Saint-LouisCNRS, GDR3697 “Microenvironment of tumor niches”Université Paris Cité, BIOSCAR Inserm U1132, Department of Rheumatology and Reference Center for Rare Bone Diseases, AP-HP Hospital LariboisièreUniversité Paris Cité, BIOSCAR Inserm U1132, Department of Rheumatology and Reference Center for Rare Bone Diseases, AP-HP Hospital LariboisièreUniversité Paris Cité, BIOSCAR Inserm U1132, Department of Rheumatology and Reference Center for Rare Bone Diseases, AP-HP Hospital LariboisièreUniversité Paris Cité, BIOSCAR Inserm U1132, Department of Rheumatology and Reference Center for Rare Bone Diseases, AP-HP Hospital LariboisièreUniversité Paris Cité, Institut de Recherche Saint-LouisCNRS, GDR3697 “Microenvironment of tumor niches”CNRS, GDR3697 “Microenvironment of tumor niches”CNRS, GDR3697 “Microenvironment of tumor niches”Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, NIHOPALE Carnot Institute, The Organization for Partnerships in Leukemia, Hôpital Saint-LouisUniversité Côte d’Azur, CNRSMolecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, NIHUniversité Paris Cité, BIOSCAR Inserm U1132, Department of Rheumatology and Reference Center for Rare Bone Diseases, AP-HP Hospital LariboisièreUniversité Paris Cité, Institut de Recherche Saint-LouisUniversité Côte d’Azur, CNRSUniversité Paris Cité, Institut de Recherche Saint-LouisAbstract 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.https://doi.org/10.1038/s41467-023-37791-4 |
| spellingShingle | 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 Karl Balabanian WHIM Syndrome-linked CXCR4 mutations drive osteoporosis Nature Communications |
| title | WHIM Syndrome-linked CXCR4 mutations drive osteoporosis |
| title_full | WHIM Syndrome-linked CXCR4 mutations drive osteoporosis |
| title_fullStr | WHIM Syndrome-linked CXCR4 mutations drive osteoporosis |
| title_full_unstemmed | WHIM Syndrome-linked CXCR4 mutations drive osteoporosis |
| title_short | WHIM Syndrome-linked CXCR4 mutations drive osteoporosis |
| title_sort | whim syndrome linked cxcr4 mutations drive osteoporosis |
| url | https://doi.org/10.1038/s41467-023-37791-4 |
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