Mechanisms modulating inflammatory osteolysis: A review with insights into therapeutic targets

Abstract

Inflammatory osteolysis is a relatively frequent and incapacitating complication of rheumatoid arthritis and multiple other inflammation-associated bone diseases. It is thought to operate through an ultimate common pathway of accelerated osteoclast recruitment and activation under the control of cytokines produced in the inflammatory environment. Over the past decade, there have been major advances in our understanding of the mechanisms of osteoclastogenesis. It is now clear that the interaction of receptor activator NF-κB (RANK) and its ligand, RANKL, plays a central role in osteoclast formation and activity. Therefore, understanding osteoclastogenesis offers new pathways for potential therapeutic intervention in inflammatory osteolysis. The success of anti-tumor necrosis factor-α and interleukin-1 therapy highlights the central role that these specific cytokines play in this disease. This review outlines our current understanding of the mechanisms mediating inflammatory osteolysis and highlights potential therapeutic strategies.

Introduction

Destructive erosion of bone or osteolysis is a major complication of inflammatory conditions such as rheumatoid arthritis (RA), periodontal disease, and periprosthetic osteolysis. RA is an autoimmune disease that affects approximately 1.0% of US adults, with a female to male ratio of 2.5 to 1 [52]. Its hallmark is progressive joint destruction which causes major morbidity. The etiology of RA is largely unclear. The combination of genetic susceptibility with environmental factors is considered to play a role in the initiation of an immunologic response against the synovium. Periodontal disease is highly prevalent and can affect up to 90% of the world's population. It is well known as the leading cause of tooth loss in adults [72]. Despite its prevalence, little is known about the mechanism by which periodontal bone erosion occurs, although host response to pathogenic microorganisms present in the mouth appears to trigger the process. In addition, genetic and environmental factors are also thought to contribute to the cause of this disease [72]. Periprosthetic osteolysis is caused by chronic bone resorption around exogenous implant devices until fixation is lost [28], and is considered as resulting from an innate immune response to wear-debris particles, with little contribution by components of the acquired immune system [22].

Although these conditions are initiated by distinct causes and progress by alternative pathways, the important common factor(s) in the pathological process of these diseases are over-production of proinflammatory cytokines and excessive destruction of bone by osteoclasts near the site of inflammation. The bone erosion seen in these conditions is largely localized to the inflamed tissues, distinct from systemic, hormonally regulated bone pathologies, such as osteoporosis. These inflamed tissues, found in many of these diseases, also produce proinflammatory cytokines, i.e., TNF-α, IL-1, and IL-6, that are, in turn, involved in osteoclast differentiation signaling and bone-resorbing activities. Thus, inflammatory osteolysis is the product of enhanced osteoclast recruitment and activation prompted by proinflammatory cytokines. The osteoclast, which is the sole bone-resorbing cell, is therefore central to the pathogenesis of inflammatory osteolysis. Understanding the mechanisms by which osteoclasts resorb bone and the cytokines that regulate their differentiation and activity provides mechanism-based potential therapeutic targets to prevent inflammatory bone loss.