Preventing periprosthetic osteolysis in aging populations through lymphatic activation and stem cell-associated secretory phenotype inhibition

• Published in: Communications biology 2024-08, Vol.7 (1), p.962-13, Article 962
• Main Authors: Zhao, Chen, Rong, Kewei, Liu, Pengcheng, Kong, Keyu, Li, Haikuo, Zhang, Pu, Chen, Xuzhuo, Fu, Qiang, Wang, Xiaoqing
• Format: Article
• Language: English
• Subjects: 13/1; 13/44; 14/1; 14/19; 631/532/7; 692/699/578; Aging; Animals; Biomedical and Life Sciences; Bone implants; Cell activation; Cell differentiation; Cell Differentiation - drug effects; Cell proliferation; Endothelial cells; External stimuli; Life Sciences; Life span; Lymphatic system; Lymphatic Vessels - drug effects; Lymphatic Vessels - metabolism; Male; Mesenchymal stem cells; Mesenchymal Stem Cells - drug effects; Mesenchymal Stem Cells - metabolism; Mice; Mice, Inbred C57BL; Osteoclastogenesis; Osteoclasts; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteolysis; Osteolysis - prevention & control; Phenotype; Phenotypes; Skull - drug effects; Skull - pathology; Titanium; Titanium alloys; Tumor necrosis factor-α; Vascular endothelial growth factor; Vascular endothelial growth factor C; Vascular Endothelial Growth Factor C - genetics; Vascular Endothelial Growth Factor C - metabolism; Vascular Endothelial Growth Factor Receptor-3 - genetics; Vascular Endothelial Growth Factor Receptor-3 - metabolism; Vascular endothelial growth factor receptors
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-024-06664-x

With increases in life expectancy, the number of patients requiring joint replacement therapy and experiencing periprosthetic osteolysis, the most common complication leading to implant failure, is growing or underestimated. In this study, we found that osteolysis progression and osteoclast differentiation in the surface of the skull bone of adult mice were accompanied by significant expansion of lymphatic vessels within bones. Using recombinant VEGF-C protein to activate VEGFR3 and promote proliferation of lymphatic vessels in bone, we counteracted excessive differentiation of osteoclasts and osteolysis caused by titanium alloy particles or inflammatory cytokines LPS/TNF-α. However, this effect was not observed in aged mice because adipogenically differentiated mesenchymal stem cells (MSCs) inhibited the response of lymphatic endothelial cells to agonist proteins. The addition of the JAK inhibitor ruxolitinib restored the response of lymphatic vessels to external stimuli in aged mice to protect against osteolysis progression. These findings suggest that inhibiting SASP secretion by adipogenically differentiated MSCs while activating lymphatic vessels in bone offers a new method to prevent periprosthetic osteolysis during joint replacement follow-up. VEGF-C activation counters osteolysis in young mice, but JAK inhibitor ruxolitinib is needed to restore lymphatic response and prevent periprosthetic osteolysis in aged mice.