The complex mechanistic network of periprosthetic osteolysis: Integration from inflammatory response and tissue...

Periprosthetic osteolysis (PPO) is the main pathophysiological mechanism responsible for aseptic loosening of a prosthesis following a total joint arthroplasty, adversely affecting long-term prosthetic fixation and clinical outcomes. The pathogenesis is primarily rooted in a cascade of biological responses induced by wear particles produced at the prosthesis-bone interface. These particles are identified by pattern recognition receptors (PRRs) on the surface of macrophages, which trigger the activation of signal transduction pathways, including the TLR/NF-κB pathway and the NLRP3 inflammasome. These events lead to the release of multiple pro-inflammatory cytokines, thereby initiating a chronic local inflammatory process, which then modulates the RANKL/RANK/OPG axis, resulting in the loss of the dynamic homeostatic balance of bone metabolism. Recent evidence has shown that PPO is a complicated pathophysiological process that encompasses multiple contributing factors. In addition to wear particles, other tissue stressors (e.g., mechanical stress, hypoxia, oxidative stress) associated with the prosthesis act in concert to alter cellular fates in mesenchymal stromal cells (MSCs), bone marrow-derived macrophages (BMMs), and osteoblasts, which include cellular senescence, apoptosis, pyroptosis, and autophagy, leading to significant amplification of inflammatory and bone resorption-associated processes. Furthermore, these inflammatory processes initiate several signaling pathways that together establish a complicated regulatory network that works together to coordinate the progression of PPO. Among these signals, the RANKL/RANK/OPG axis acts as a central regulatory node by activating adaptive MAPK and NF-κB signaling pathways to coordinate local inflammatory responses and osteoclast differentiation, in addition to blocking osteoblast differentiation via Wnt/β-catenin signaling pathways, resulting in the loss of bone to create a pathological state of increased resorption and decreased formation of bone. Therefore, this review is designed to integrate new findings and to form a composite mechanistic framework that describes the immuno-inflammatory response, tissue stress, altered cell fate, and staged signaling pathways. It systematically breaks down the interaction among these factors and how they culminate in a loss of bone homeostasis, which informs our understanding of how PPO progresses. Thereby, this research enhances our ability to increase the longevity of artificial joints in order to improve the post-operative quality of life for patients.