Endothelial proteolytic activity and interaction with non-resorbing osteoclasts mediate bone elongation

Area of Science:

• Skeletal Biology
• Vascular Biology
• Cell Biology

Background:

• Growth plate cartilage determines mammalian skeletal element shape and size.
• The mechanisms of cartilage removal and its role in bone morphogenesis are not fully understood.

Purpose of the Study:

• To identify novel cell types and mechanisms involved in cartilage resorption during bone growth.
• To elucidate the role of endothelial cells and osteoclasts in regulating bone shape and vascularization.

Main Methods:

• Identification and characterization of a novel osteoclast subtype, vessel-associated osteoclasts (VAOs).
• Analysis of RANKL-RANK signaling between endothelial cells and VAOs.
• Investigation of the role of endothelial cell-derived proteinases (e.g., MMP9) in cartilage resorption.
• Assessment of the impact of altered blood vessel orientation on bone shape.

Main Results:

• A new osteoclast subtype, VAO, was identified, which supports blood vessel anastomosis but does not resorb cartilage.
• Endothelial cells, not VAOs, are crucial for cartilage resorption via proteinases like MMP9, directing longitudinal bone growth.
• Misorientation of angiogenic blood vessels leads to abnormal bone morphology.

Conclusions:

• Endothelial cells possess proteolytic functions essential for cartilage remodeling and directional bone growth.
• VAOs play a role in vascularization rather than direct cartilage degradation.
• This study reveals a novel mechanism of bone shaping involving endothelial cell-derived proteinases and vascular guidance, with implications for skeletal disorders.