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Descendants of hypertrophic chondrocytes promote angiogenesis by secreting THBS4 during bone growth and injury repair.

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Název: Descendants of hypertrophic chondrocytes promote angiogenesis by secreting THBS4 during bone growth and injury repair.
Autoři: Song, Shiju, Fan, Jing, Ding, Guangyu, Yin, Jinhua, Lu, Weiguang, Huang, Liangjie, Hu, Jingyan, Gong, Xueqin, Gao, Bo, Jie, Qiang, Cheah, Kathryn Song Eng, Zheng, Chao, Yang, Liu
Zdroj: Bone Research; 11/10/2025, Vol. 13 Issue 1, p1-12, 12p
Témata: NEOVASCULARIZATION, BONE growth, EXTRACELLULAR matrix proteins, WOUND healing, FATE mapping (Genetics), LABORATORY mice, CARTILAGE cells, VASCULAR endothelial cells
Abstrakt: Hypertrophic chondrocytes (HCs) could transform into osteoblastic lineage cells while the pathophysiological implications of HC transformation remain largely unknown. Here, we generated a mouse line utilizing Col10a1-Cre to induce DTA expression to genetically ablate HCs and their descendants. Col10a1-Cre; R26DTA/+ mice displayed dwarf phenotype, abnormal spongy bone, and significantly delayed drill-hole injuries healing, suggesting an indispensable role of HC lineage extension in bone growth and injury repair. Intriguingly, single-cell RNA sequencing analysis revealed the most significant loss of a cell cluster expressing multiple angiogenic factors (Pro-Angiogenic Descendants of HCs, PADs) among cells derived from Col10a1-Cre; R26DTA/+ and control femurs. In silico analysis of cell-cell communication supported Thrombospondin 4 (THBS4) as a specific angiogenic factor mediating the crosstalk between PADs and vascular endothelial cells. Concordantly, analyses using immunostaining combined with tissue clearing revealed that PADs physically contacted with endothelial cells, whereas Col10a1-Cre; R26DTA/+ mice showed defective metaphyseal and cortical vessel formation and post-injury angiogenesis along with a significant loss of THBS4. Moreover, in vitro assays showed that supplying THBS4 was sufficient to promote proliferation and tube formation of endothelial cells and rescue defective angiogenesis of Col10a1-Cre; R26DTA/+ metatarsal explants. Collectively, these findings demonstrate a critical role of PADs in bone growth and injury repair by secreting THBS4 to regulate angiogenesis. [ABSTRACT FROM AUTHOR]
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Abstrakt:Hypertrophic chondrocytes (HCs) could transform into osteoblastic lineage cells while the pathophysiological implications of HC transformation remain largely unknown. Here, we generated a mouse line utilizing Col10a1-Cre to induce DTA expression to genetically ablate HCs and their descendants. Col10a1-Cre; R26<sup>DTA/+</sup> mice displayed dwarf phenotype, abnormal spongy bone, and significantly delayed drill-hole injuries healing, suggesting an indispensable role of HC lineage extension in bone growth and injury repair. Intriguingly, single-cell RNA sequencing analysis revealed the most significant loss of a cell cluster expressing multiple angiogenic factors (Pro-Angiogenic Descendants of HCs, PADs) among cells derived from Col10a1-Cre; R26<sup>DTA/+</sup> and control femurs. In silico analysis of cell-cell communication supported Thrombospondin 4 (THBS4) as a specific angiogenic factor mediating the crosstalk between PADs and vascular endothelial cells. Concordantly, analyses using immunostaining combined with tissue clearing revealed that PADs physically contacted with endothelial cells, whereas Col10a1-Cre; R26<sup>DTA/+</sup> mice showed defective metaphyseal and cortical vessel formation and post-injury angiogenesis along with a significant loss of THBS4. Moreover, in vitro assays showed that supplying THBS4 was sufficient to promote proliferation and tube formation of endothelial cells and rescue defective angiogenesis of Col10a1-Cre; R26<sup>DTA/+</sup> metatarsal explants. Collectively, these findings demonstrate a critical role of PADs in bone growth and injury repair by secreting THBS4 to regulate angiogenesis. [ABSTRACT FROM AUTHOR]
ISSN:20954700
DOI:10.1038/s41413-025-00469-2