ANGPTL4 binds to the leptin receptor to regulate ectopic bone formation.

Area of Science:

• Endocrinology
• Skeletal Biology
• Molecular Biology

Background:

• Leptin signaling through the leptin receptor (LepR) is crucial for metabolic regulation.
• Discrepancies in phenotypes between LepR-deficient (db/db) and leptin-deficient (ob/ob) mice suggest additional LepR ligands may exist.
• The role of LepR in non-metabolic processes like bone formation is not fully understood.

Purpose of the Study:

• To investigate the potential for alternative LepR ligands involved in processes beyond metabolism.
• To identify novel regulators of heterotopic ossification (HO).
• To elucidate the molecular mechanisms by which LepR signaling influences chondrogenesis and bone formation.

Main Methods:

• Comparative analysis of tenotomy-induced heterotopic ossification (HO) in db/db and ob/ob mouse models.
• Ligand screening to identify factors elicited from brown adipose tissue post-tenotomy.
• Immunohistochemical analysis to detect ANGPTL4 binding to LepR on PRRX1+ mesenchymal cells.
• Genetic manipulation including disruption of LepR in specific cell populations and ANGPTL4 deletion.
• Assessment of chondrogenesis and HO formation in genetically modified mice.

Main Results:

• db/db mice, but not ob/ob mice, exhibited defects in tenotomy-induced HO, indicating a non-leptin-dependent LepR function.
• Angiopoietin-like protein 4 (ANGPTL4) was identified as a stress and fasting-induced factor released after tenotomy.
• ANGPTL4 binds to LepR on PRRX1+ mesenchymal cells at the HO site, promoting chondrogenesis and HO.
• Genetic disruption of LepR in PRRX1+ cells, ablation of LepR+ cells, or ANGPTL4 deletion significantly impaired chondrogenesis and HO.

Conclusions:

• Angiopoietin-like protein 4 (ANGPTL4) is identified as a novel ligand for the leptin receptor (LepR).
• ANGPTL4-LepR signaling in PRRX1+ mesenchymal cells is critical for the development of acquired heterotopic ossification (HO).
• These findings reveal a new role for LepR beyond leptin signaling in regulating skeletal development and acquired bone formation.