Lymphatic Endothelial Cells Produce M-CSF, Causing Massive Bone Loss in Mice

Area of Science:

• Bone biology
• Vascular biology
• Rare diseases

Background:

• Gorham-Stout disease (GSD) is a rare, aggressive bone disorder of unknown etiology.
• GSD involves osteolysis and lymphatic vessel invasion within bone marrow.
• Current therapies and animal models for GSD are lacking.

Purpose of the Study:

• To investigate the role of lymphatic endothelial cells (LECs) in GSD osteolysis.
• To determine if LECs promote osteoclast (OC) formation and bone resorption.
• To establish a mouse model for studying GSD.

Main Methods:

• Co-culture of mouse LECs with osteoclast precursors.
• In vivo injection of LECs into wild-type mouse tibias.
• Assessment of bone destruction using X-ray, micro-CT, and histology.
• Analysis of M-CSF levels and blockade of M-CSF signaling.

Main Results:

• LECs significantly enhanced RANKL-mediated osteoclastogenesis and bone resorption in vitro.
• LECs secrete macrophage colony-stimulating factor (M-CSF), which drives OC formation.
• Intra-tibial LEC injection in mice caused massive osteolysis and increased M-CSF levels.
• Inhibition of M-CSF signaling reduced bone destruction in the mouse model.

Conclusions:

• LECs contribute to GSD pathogenesis by secreting M-CSF, promoting osteoclast activity and bone destruction.
• Targeting M-CSF signaling presents a potential therapeutic strategy for GSD.
• Tibial LEC injection provides a valuable mouse model for GSD research.