Controlled mechanical loading improves bone regeneration by regulating type H vessels in a S1Pr1-dependent manner
Chengyu Yang1,2, Yang Liu1,2, Ziyan Wang1,2
1Department of Biomedical Engineering, College of Engineering, Southern University of Science and Technology, Shenzhen, China.
Summary
Controlled mechanical loading enhances bone repair by targeting specific blood vessels. This process involves sphingosine 1-phosphate receptor 1 (S1Pr1) and Type H vessels, crucial for bone formation and healing.
Area of Science:
- Biomedical Engineering
- Regenerative Medicine
- Orthopedics
Background:
- Delayed unions and non-unions affect approximately 10% of fractures despite optimal treatment.
- Controlled mechanical loading promotes osteogenic cell activity during bone matrix deposition.
- Bone vascular networks, particularly Type H vessels, are critical for guiding bone formation and coupling angiogenesis with osteogenesis.
Purpose of the Study:
- To investigate the role of sphingosine 1-phosphate receptor 1 (S1Pr1) in mechanical loading-induced bone repair.
- To elucidate the mechanism by which controlled mechanical loading regulates Type H vessels to promote bone formation.
Main Methods:
- Utilized a stabilized tibial defect model in rodents to apply controlled anabolic mechanical loading.
- Employed deep tissue imaging to observe S1Pr1 expression in blood vessels within the bone defect.
- Investigated the effects of S1Pr1 antagonism (W146) and activation (FTY720) on bone repair and cellular responses.
- Assessed YAP nuclear translocation in endothelial cells (ECs) in vitro and in vivo using siRNA and pharmacological inhibitors.
Main Results:
- Mechanical loading significantly upregulated S1Pr1, predominantly in blood vessels within the defect.
- S1Pr1 antagonism inhibited the anabolic effects of mechanical loading on bone repair.
- Mechanical loading and S1Pr1 activation induced YAP nuclear translocation in ECs, a key mechanotransduction event.
- Inhibition of S1Pr1 reduced loading-induced YAP translocation and angiogenic gene expression.
- In vivo, mechanical loading increased YAP translocation in Type H vessels, an effect blunted by S1Pr1 antagonism.
- S1Pr1 agonist FTY720 administration promoted bone and Type H vessel volume, mimicking mechanical stimulation.
Conclusions:
- Controlled anabolic mechanical loading enhances bone repair primarily through Type H vessels.
- This process is dependent on the sphingosine 1-phosphate receptor 1 (S1Pr1) pathway.
- Targeting S1Pr1 presents a potential therapeutic strategy for improving fracture healing.
