Monomeric C-Reactive Protein Binds and Neutralizes Receptor Activator of NF-κB Ligand-Induced Osteoclast Differentiation.

Zhe-Kun Jia,Hai-Yun Li,Lawrence Albert Potempa,Yi Wu,Shang-Rong Ji,Yu-Lin Liang

doi:10.3389/fimmu.2018.00234

Abstract

C-reactive protein (CRP) is an established marker of rheumatoid arthritis (RA) but with ill-defined actions in the pathogenesis. Here, we show that CRP regulates the differentiation of osteoclasts, a central mediator of joint inflammation and bone erosion in RA, in a conformation- and receptor activator of NF-κB ligand (RANKL)-dependent manner. CRP in the native conformation is ineffective, whereas the monomeric conformation (mCRP) actively modulates osteoclast differentiation through NF-κB and phospholipase C signaling. Moreover, mCRP can bind RANKL, the major driver of osteoclast differentiation, and abrogate its activities. The binding and inhibition of RANKL are mediated by the cholesterol binding sequence (CBS) of mCRP. Corroborating the in vitro results, CRP knockout exacerbates LPS-induced bone resorption in mice. These results suggest that mCRP may be protective in joint inflammation by inhibiting pathological osteoclast differentiation and that the CBS peptide could be exploited as a potential RANKL inhibitor.

Highlights

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic joint inflammation and bone erosion [1]
C-reactive protein (CRP) in different conformations exhibit distinct or even contrasting activities [14,15,16,17,18], which may account for the controversies on its role in osteoclast differentiation [12, 13]
Treating Raw cells with Native CRP (nCRP) for 2 days did not alter the expression of osteoclast maker genes TRAP and Cathepsin K (Figure 1A)

Summary

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic joint inflammation and bone erosion [1]. Autoimmunity in RA is likely triggered first at mucosal sites in response to environmental insults but needs to target joints to initiate the disease. Osteoclasts play a major part in homing systemic autoimmunity to joints [2]. These cells locate in the bone compartments, and are differentiated from myeloid precursors driven primarily by receptor activator of NF-κB ligand (RANKL) [3]. They respond to autoantibodies frequently found in RA by secreting cytokines that evoke and amplify joint inflammation. Modulating the differentiation and actions of osteoclasts represents a promising strategy for treatment of RA [2, 5, 6]

Methods

Results

Conclusion