Increased expression of CXCL2 in ACPA-positive rheumatoid arthritis and its role in osteoclastogenesis

Abstract

Summary Anti-citrullinated protein/peptide antibodies (ACPA) play important roles in the pathogenesis of rheumatoid arthritis (RA). ACPA-positive (ACPA+) and ACPA-negative (ACPA−) RA were suggested to be different disease subsets, with distinct differences in genetic variation and clinical outcomes. The aims of the present study were to compare gene expression profiles in ACPA+ and ACPA− RA, and to identify novel candidate gene signatures that might serve as therapeutic targets. Comprehensive transcriptome analysis of peripheral blood mononuclear cells (PBMCs) from ACPA+ and ACPA− RA patients and healthy controls was performed via RNA sequencing. A validation cohort was used to further investigate differentially expressed genes via polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Spearman's correlation test was used to evaluate the correlation of differentially expressed genes and the clinical and laboratory data of the patients. The role of differentially expressed genes in osteoclastogenesis was further investigated. Expression of C-X-C motif chemokine ligand 2 (CXCL2) was significantly increased in ACPA+ RA than in ACPA− RA, which was validated in PBMCs and serum. CXCL2 promoted the migration of CD14+ monocytes and increased osteoclastogenesis in RA patients. RAW264.7 macrophages were used to investigate specific mechanisms, and the results suggested that CXCL2 stimulated osteoclastogenesis via extracellular receptor kinase (ERK) mitogen-activated protein kinase (MAPK) and nuclear factor kappa B pathways. In conclusion, CXCL2 was highly expressed in ACPA+ RA than in ACPA− RA. CXCL2 promoted osteoclastogenesis and was related to bone erosion in RA, which suggests that the blockade of CXCL2 might be a novel strategy for the treatment of RA.

Apoptotic mesenchymal stromal cells support osteoclastogenesis while inhibiting multinucleated giant cells formation in vitro

“…The major mediators of MSCs’ stimulatory effect towards osteoclastogenesis seemed to be IL-8/CXCL-8 and other CXCR-2 ligands (CXCL-1, -2 and -3). This is supported by previous in vitro studies reporting positive effects of these CXCL chemokines on monocytes migration and osteoclasts differentiation 36 – 38 . Given the complexity of MSCs’ secretome, these proteins may not be the only ones involved, and additional studies are warranted to identify additional players.…”

Abatacept downregulates Fcγ receptor I on circulating monocytes: a potential therapeutic mechanism in patients with rheumatoid arthritis

“…Since it has been reported that macrophages derived from the peripheral blood monocytes of RA patients produce inflammatory cytokines and chemokines after binding to the ACPA immune complex [ 22 ], abatacept-induced downregulation of CD64/FcγRI on monocytes may suppress ACPA immune complex-induced production of inflammatory cytokines/chemokines in patients with ACPA-positive RA. To test this hypothesis, peripheral blood monocytes were isolated from 19 RA patients who were ACPA-positive and treatment-naive and were cultured with ACPA immune complexes in the absence (mock) or presence of abatacept.…”

The Impact of Seropositivity on Bone Mineral Density in Rheumatoid Arthritis - A 3-year Prospective Observational Study

“…Later on, Krishnamurthy et al demonstrated that polyclonal ACPAs enhance osteoclast differentiation through a PADdependent IL-8-mediated autocrine loop [33]. A recent study also illustrated that ACPA-positive RA has a higher expression of CXCL2 (which can mediate the osteoclastogenesis in vitro) than ACPA-negative RA [34]. Monocyte lineage challenge with ACPA or RF autoantibodies can induce production of the cytokines TNF-α, IL-1β, IL-6, and IL-8 which are directly able to enhance osteoclast formation [35].…”