Abstract
Lipoteichoic acid (LTA) is a cell wall component of Gram-positive bacteria. Limited data suggest that LTA is beneficial for bone regeneration in vitro. Thus, we used a mouse model of femoral defects to explore the effects of LTA on bone healing in vivo. Micro-computed tomography analysis and double-fluorochrome labeling were utilized to examine whether LTA can accelerate dynamic bone formation in vivo. The effects of LTA on osteoblastogenesis and osteoclastogenesis were also studied in vitro. LTA treatment induced prompt bone bridge formation, rapid endochondral ossification, and accelerated healing of fractures in mice with femoral bone defects. In vitro, LTA directly enhanced indicators of osteogenic factor-induced MC3T3-E1 cell differentiation, including alkaline phosphatase activity, calcium deposition and osteopontin expression. LTA also inhibited osteoclast activation induced by receptor activator of nuclear factor-kappa B ligand. We identified six molecules that may be associated with LTA-accelerated bone healing: monocyte chemoattractant protein 1, chemokine (C-X-C motif) ligand 1, cystatin C, growth/differentiation factor 15, endostatin and neutrophil gelatinase-associated lipocalin. Finally, double-fluorochrome, dynamic-labeling data indicated that LTA significantly enhanced bone-formation rates in vivo. In conclusion, our findings suggest that LTA has promising bone-regeneration properties.
Highlights
Delayed bone healing leads to a diminished quality of life, a personal financial burden and increased medical care costs
In the sham-treated group of femoral-defect mice, significant gaps were still observed on Day 7 after surgery, and cancellous bone formation was seen on Day 14
Staphylococcal Lipoteichoic acid (LTA) inhibited the phosphorylation of extracellular signal-regulated kinase and c-Jun N-terminal kinase in Ocl precursors, which were treated with macrophage colony-stimulating factor and RANKL, concomitantly with a decreased DNA-binding activity of activator protein 1 [28]
Summary
Delayed bone healing leads to a diminished quality of life, a personal financial burden and increased medical care costs. Novel therapies to enhance bone healing are sorely needed. Current state-of-the-art therapeutic methods for impaired bone healing can be divided into four categories: conservative therapy, surgical therapy, molecular targets for local or systemic applications and novel bone substitute grafts. Exposure to GP bacteria-derived LTA inhibits the differentiation of bone marrow-derived macrophages (BMMs) to osteoclasts (Ocls) [15]. We generated a bone-defect mouse model to examine whether LTA treatment can accelerate bone healing. We found that LTA treatment induced bone bridge formation, endochondral ossification and healing of fractures in mice with femoral bone defects. We found that LTA directly enhanced indicators of osteogenic factor-induced MC3T3-E1 cell differentiation. We observed that LTA inhibited NF-κB-induced Ocl activation in vitro and identified six molecules that may be related to LTA-induced bone healing. Our findings suggest that LTA is a promising molecule for promoting immuno-modulatory bone regeneration in bone biomaterials
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