DOI: 10.1073/pnas.2310685120 ISSN: 0027-8424

ANGPTL4 binds to the leptin receptor to regulate ectopic bone formation

Hongling Hu, Sheng Luo, Pinglin Lai, Mingqiang Lai, Linlin Mao, Sheng Zhang, Yuanjun Jiang, Jiaxin Wen, Wu Zhou, Xiaolin Liu, Liang Wang, Minjun Huang, Yanjun Hu, Xiaoyang Zhao, Laixin Xia, Weijie Zhou, Yu Jiang, Zhipeng Zou, Anling Liu, Bin Guo, Xiaochun Bai
  • Multidisciplinary

Leptin protein was thought to be unique to leptin receptor (LepR), but the phenotypes of mice with mutation in LepR [ db/db (diabetes)] and leptin [ ob/ob (obese)] are not identical, and the cause remains unclear. Here, we show that db/db , but not ob/ob , mice had defect in tenotomy-induced heterotopic ossification (HO), implicating alternative ligand(s) for LepR might be involved. Ligand screening revealed that ANGPTL4 (angiopoietin-like protein 4), a stress and fasting-induced factor, was elicited from brown adipose tissue after tenotomy, bound to LepR on PRRX1 + mesenchymal cells at the HO site, thus promotes chondrogenesis and HO development. Disruption of LepR in PRRX1 + cells, or lineage ablation of LepR + cells, or deletion of ANGPTL4 impeded chondrogenesis and HO in mice. Together, these findings identify ANGPTL4 as a ligand for LepR to regulate the formation of acquired HO.

More from our Archive