Interplay between Inflammation and Pathological Bone Resorption: Insights into Recent Mechanisms and Pathways in Related Diseases for Future Perspectives

Abstract

Bone is a mineralized and elastic connective tissue that provides fundamental functions in the human body, including mechanical support to the muscles and joints, protection of vital organs and storage of minerals. Bone is a metabolically active organ that undergoes continuous remodeling processes to maintain its architecture, shape, and function throughout life. One of the most important medical discoveries of recent decades has been that the immune system is involved in bone remodeling. Indeed, chronic inflammation has been recognized as the most significant factor influencing bone homeostasis, causing a shift in the bone remodeling process toward pathological bone resorption. Bone osteolytic diseases typified by excessive bone resorption account for one of the greatest causes of disability worldwide, with significant economic and public health burdens. From this perspective, we discuss the recent findings and discoveries highlighting the cellular and molecular mechanisms that regulate this process in the bone microenvironment, in addition to the current therapeutic strategies for the treatment of osteolytic bone diseases.

Keywords: bone; bone osteolytic diseases; inflammation; pathological bone resorption; remodeling.

Figure 1

Schematic diagram illustrating the cellular entities in bone microenvironment. OB: osteoblast, OC: osteoclast, OS: osteocytes, osteomacs: osteal macrophage.

Figure 2

Illustration of how immune factors impact on osteoclastogenesis. Immune cells produce a variety of factors that promote osteoclastogenesis via both canonical and non-canonical pathways. They activate TRAFs that initiate the action of NFκB and the c-src /PI 3-kinase/Akt signal transduction pathways. These lead to the activation of downstream molecules c-Fos, Fos B, FRA-1, FRA-2 and c-Jun, JunB, JunD, followed by the induction of the master regulator of osteoclast differentiation NFATc1. Some of the other immune factors are able to initiate the autoregulation system for RANKL signaling by inducing the expression of transcriptional repressors to restrain cell differentiation.

Figure 3

Schematic illustration of potential role of osteomacs in bone remodeling. Osteomacs can potentially produce inflammatory factors that promote osteoclastogenesis and apoptosis of osteoblasts and osteocytes. They are also able to produce anti-inflammatory and growth factors that positively regulate the function of osteoblasts and osteocytes.

Figure 4

Potential regulatory role of SCFAs in inflammation and bone remodeling. SCFA, such as butyrate and propionate, inhibit osteoclastogenesis and promote differentiation of CD4 T cell into regulatory T cells (Tregs) and macrophages into an anti-inflammatory phenotype that facilitate an anabolic state in the bone microenvironment.