The role of C5a-C5aR1 axis in bone pathophysiology: A mini-review

Abstract

Bone remodeling is a physiological, dynamic process that mainly depends on the functions of 2 cell types: osteoblasts and osteoclasts. Emerging evidence suggests that complement system is crucially involved in the regulation of functions of these cells, especially during inflammatory states. In this context, complement component 5a (C5a), a powerful pro-inflammatory anaphylatoxin that binds the receptor C5aR1, is known to regulate osteoclast formation and osteoblast inflammatory responses, and has thus been proposed as potential therapeutic target for the treatment of inflammatory bone diseases. In this review, we will analyze the role of C5a-C5aR1 axis in bone physiology and pathophysiology, describing its involvement in the pathogenesis of some of the most frequent inflammatory bone diseases such as rheumatoid arthritis, and also in osteoporosis and bone cancer and metastasis. Moreover, we will examine C5aR1-based pharmacological approaches that are available and have been tested so far for the treatment of these conditions. Given the growing interest of the scientific community on osteoimmunology, and the scarcity of data regarding the role of C5a-C5aR1 axis in bone pathophysiology, we will highlight the importance of this axis in mediating the interactions between skeletal and immune systems and its potential use as a therapeutic target.

Keywords: C5a; C5aR1; bone; osteoblasts; osteoclasts; rheumatoid arthritis.

FIGURE 1

The role of C5a as a modulator of osteoblast-osteoclast interplay. 1) Activated complement system leads to the generation of C5a which can bind to C5aR1/2 on osteoblasts; 2) once activated by C5a, osteblasts start to release IL-6 and RANKL, thus inducing 3) osteoclastogenesis and bone resorption as well as differentiation of osteoclast progenitors; 4) activated osteoblasts can also secrete other chemokines and cytokines, such as MCP-1, CCL2 and IL-8, which in turn act on osteoblasts inducing a non-proliferative osteoclast-promoting state; 5) C5a also regulates the first phase of osteoclastogenesis maturation. Created with BioRender.com.

FIGURE 2

C5a in rheumatoid arthritis. In secondary tissues of RA patients, production of autoantibodies 1) activates inflammation and attracts immune cells 2), such as T and B lymphocytes, neutrophils and monocytes, to the inflammation site. The release of proinflammatory molecules 3) drives the proliferation of synovial tissue fibroblasts, which can contribute to the increase of C5a levels in the synovial fluid (SF) 4). C5a contributes to additional immune cell recruitment 5) and activation: neutrofils can undergo NETosis releasing proteaseses (i.e., MPO, elastase, MMP-9), while macrophages can release inflammatory proteins (i.e., MIP-1α, MIP-2α and IL-8). The release of proteases and proinflammatory proteins supports cartilage degradation, joint inflammation and bone remodeling, amplyfing the inflammatory state 6). Created with BioRender.com.