Osteoblasts-derived exosomes as potential novel communicators in particle-induced periprosthetic osteolysis.

The inflammatory response to wear particles derived from hip prothesis is considered a hallmark of periprosthetic osteolysis, which can ultimately lead to the need for revision surgery. Exosomes (Exos) have been associated with various bone pathologies, and there is increasing recognition in the literature that they actively transport molecules throughout the body. The role of wear particles in osteoblast-derived Exos is unknown, and the potential contribution of Exos to osteoimmune communication and periprosthetic osteolysis niche is still in its infancy. Given this, we investigate how titanium dioxide nanoparticles (TiO2 NPs), similar in size and composition to prosthetic wear particles, affect Exos biogenesis. Two osteoblastic cell models commonly used to study the response of osteoblasts to wear particles were selected as a proof of concept. The contribution of Exos to periprosthetic osteolysis was assessed by functional assays in which primary human macrophages were stimulated with bone-derived Exos. We demonstrated that TiO2 NPs enter multivesicular bodies, the nascent of Exos, altering osteoblast-derived Exos secretion and molecular cargo. No significant differences were observed in Exos morphology and size. However, functional assays reveal that Exos cargo enriched in uPA stimulates macrophages to a mixed M1 and M2 phenotype, inducing the release of pro- and anti-inflammatory signals characteristic of periprosthetic osteolysis. In addition, we demonstrated the expression of uPA in exosomes derived from the urine of patients with osteolysis. These results suggest that uPA can be a potential biomarker of osteolysis. In the future, uPa may serve as a possible non-invasive biomarker to identify patients at risk for peri-implant osteolysis.

Titanium dioxide nanoparticles affect osteoblast-derived exosome cargos and impair osteogenic differentiation of human mesenchymal stem cells.

Titanium (Ti) and its alloys are the most widely used metallic biomaterials in total joint replacement; however, increasing evidence supports the degradation of its surface due to corrosion and wear processes releasing debris (ions, and micro and nanoparticles) and contribute to particle-induced osteolysis and implant loosening. Cell-to-cell communication involving several cell types is one of the major biological processes occurring during bone healing and regeneration at the implant-bone interface. In addition to the internal response of cells to the uptake and intracellular localization of wear debris, a red flag is the ability of titanium dioxide nanoparticles (mimicking wear debris) to alter cellular communication with the tissue background, disturbing the balance between osseous tissue integrity and bone regenerative processes. This study aims to understand whether titanium dioxide nanoparticles (TiO2 NPs) alter osteoblast-derived exosome (Exo) biogenesis and whether exosomal protein cargos affect the communication of osteoblasts with human mesenchymal stem/stromal cells (HMSCs). Osteoblasts are derived from mesenchymal stem cells coexisting in the bone microenvironment during development and remodelling. We observed that TiO2 NPs stimulate immature osteoblast- and mature osteoblast-derived Exo secretion that present a distinct proteomic cargo. Functional tests confirmed that Exos derived from both osteoblasts decrease the osteogenic differentiation of HMSCs. These findings are clinically relevant since wear debris alter extracellular communication in the bone periprosthetic niche, contributing to particle-induced osteolysis and consequent prosthetic joint failure.

Trojan-Like Internalization of Anatase Titanium Dioxide Nanoparticles by Human Osteoblast Cells.

Dentistry and orthopedics are undergoing a revolution in order to provide more reliable, comfortable and long-lasting implants to patients. Titanium (Ti) and titanium alloys have been used in dental implants and total hip arthroplasty due to their excellent biocompatibility. However, Ti-based implants in human body suffer surface degradation (corrosion and wear) resulting in the release of metallic ions and solid wear debris (mainly titanium dioxide) leading to peri-implant inflammatory reactions. Unfortunately, our current understanding of the biological interactions with titanium dioxide nanoparticles is still very limited. Taking this into consideration, this study focuses on the internalization of titanium dioxide nanoparticles on primary bone cells, exploring the events occurring at the nano-bio interface. For the first time, we report the selective binding of calcium (Ca), phosphorous (P) and proteins from cell culture medium to anatase nanoparticles that are extremely important for nanoparticle internalization and bone cells survival. In the intricate biological environment, anatase nanoparticles form bio-complexes (mixture of proteins and ions) which act as a kind of 'Trojan-horse' internalization by cells. Furthermore, anatase nanoparticles-induced modifications on cell behavior (viability and internalization) could be understand in detail. The results presented in this report can inspire new strategies for the use of titanium dioxide nanoparticles in several regeneration therapies.