Extracellular Matrix Degradation and Tissue Remodeling in Periprosthetic Loosening and Osteolysis: Focus on Matrix Metalloproteinases, Their Endogenous Tissue Inhibitors, and the Proteasome

Abstract

The leading complication of total joint replacement is periprosthetic osteolysis, which often results in aseptic loosening of the implant, leading to revision surgery. Extracellular matrix degradation and connective tissue remodeling around implants have been considered as major biological events in the periprosthetic loosening. Critical mediators of wear particle-induced inflammatory osteolysis released by periprosthetic synovial cells (mainly macrophages) are inflammatory cytokines, chemokines, and proteolytic enzymes, mainly matrix metalloproteinases (MMPs). Numerous studies reveal a strong interdependence of MMP expression and activity with the molecular mechanisms that control the composition and turnover of periprosthetic matrices. MMPs can either actively modulate or be modulated by the molecular mechanisms that determine the debris-induced remodeling of the periprosthetic microenvironment. In the present study, the molecular mechanisms that control the composition, turnover, and activity of matrix macromolecules within the periprosthetic microenvironment exposed to wear debris are summarized and presented. Special emphasis is given to MMPs and their endogenous tissue inhibitors (TIMPs), as well as to the proteasome pathway, which appears to be an elegant molecular regulator of specific matrix macromolecules (including specific MMPs and TIMPs). Furthermore, strong rationale for potential clinical applications of the described molecular mechanisms to the treatment of periprosthetic loosening and osteolysis is provided.

Potential proinflammatory and osteogenic effects of dicalcium silicate particles in vitro

“…Matrix metalloproteinases (MMPs) are capable of degrading all major components of the extracellular matrix [36] . TIMPs regulate MMP activity [37] .…”

M1 and M2 Macrophages: The Chicken and the Egg of Immunity

“…Other products, like IL-6 and TNF or IL-1 and IL-10, are only loosely associated with M1 or M2 responses, respectively. However, these cytokines have been observed in both M1- and M2-type responses, as have NADPH oxidases, and various matrix-remodeling metalloproteinases [4, 28, 74–76]. Such molecules indicate the presence of macrophages, but should not be strictly ascribed to M1/inhibit or M2/heal activity as has been done [7, 63].…”

A Brief Introduction to Proteinases

“…Proteasomes are the main mediators of intracellular degradation of a wide variety of cellular proteins and they are implicated in several physiological and pathological cellular functions. 6,7 The proteasome pathway is involved in matrix degradation by several mechanisms, which include both transcriptional and posttranslational mechanisms. By controlling the concentration and turnover of several ECM components, the proteasome pathway contributes to extracellular proteolytic events by modulating the expression and activity of MMPs and their endogenous inhibitors (see the following).…”

“…By controlling the concentration and turnover of several ECM components, the proteasome pathway contributes to extracellular proteolytic events by modulating the expression and activity of MMPs and their endogenous inhibitors (see the following). Therefore, since matrix remodeling and degradation can be controlled by proteasome activities, proteasome modulation might be a novel therapeutic strategy in some pathologic conditions 7 and perhaps future studies may reveal additional mechanisms of their action and therapeutic strategies that target them.…”