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<p>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 <i>Col10a1-Cre</i> to induce DTA expression to genetically ablate HCs and their descendants. <i>Col10a1-Cre; R26</i><sup><i>DTA/+</i></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 <i>Col10a1-Cre; R26</i><sup><i>DTA/+</i></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 <i>Col10a1-Cre; R26</i><sup><i>DTA/+</i></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 <i>Col10a1-Cre; R26</i><sup><i>DTA/+</i></sup> metatarsal explants. Collectively, these findings demonstrate a critical role of PADs in bone growth and injury repair by secreting THBS4 to regulate angiogenesis.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月10日

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  • Shiju Song,
  • Jing Fan,
  • Guangyu Ding,
  • Jinhua Yin,
  • Weiguang Lu,
  • Liangjie Huang,
  • Jingyan Hu,
  • Xueqin Gong,
  • Bo Gao,
  • Qiang Jie,
  • Kathryn Song Eng Cheah,
  • Chao Zheng,
  • Liu Yang

摘要

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.