Université Paris Cité, Institut de Recherche Saint-Louis, INSERM U1160, Paris, France.
CNRS, GDR3697 "Microenvironment of tumor niches", Micronit, France.
Nat Commun. 2023 Apr 12;14(1):2058. doi: 10.1038/s41467-023-37791-4.
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.
WHIM 综合征是一种由 CXCR4 功能获得性突变引起的罕见免疫缺陷。在这里，我们报告了 25%的 WHIM 患者存在骨密度降低的情况，并且在 WHIM 小鼠模型中存在导致骨质疏松的骨缺陷。在突变小鼠中观察到骨组织失衡，表现为成骨祖细胞减少和破骨细胞数量增加。从机制上讲，受损的 CXCR4 脱敏会破坏骨骼基质/干细胞的细胞周期进程和成骨细胞分化，同时增加其促破骨细胞生成能力。WHIM 患者的原代骨髓基质细胞中存在成骨分化受损的证据。在小鼠中，慢性使用 CXCR4 拮抗剂 AMD3100 可使突变骨骼基质/干细胞的体外成骨命运正常化，并在体内逆转骨骼细胞的丢失，表明适当的 CXCR4 脱敏对于骨骼基质/干细胞的成骨特化是必需的。我们的研究提供了关于 CXCR4 信号如何调节骨骼细胞的成骨命运以及骨形成和吸收之间平衡的机制见解。
