Rheumatoid Arthritis Bone Fragility Is Associated With Upregulation of IL17 and DKK1 Gene Expression

Abstract

Our aim was to compare bone gene expression in rheumatoid arthritis (RA) and primary osteoporosis (OP) patients. Secondary aims were to determine the association of gene expression of the Wnt/β-catenin signaling pathway with inflammatory cytokines in the bone microenvironment and to assess the serum levels of Wnt/β-catenin proteins in both groups. RA patients referred for hip replacement surgery were recruited. Primary OP patients were used as controls. Gene expression of Wnt pathway mediators, matrix proteins, and pro-inflammatory cytokines were analyzed in bone samples. Bone turnover markers, inflammatory cytokines, and Wnt mediators were measured in serum. Twenty-two patients were included: 10 with RA and 12 with primary OP. The expressions of Wnt10b (p = 0.034), its co-receptor LRP6 (p = 0.041), and its negative regulator DKK1 (p = 0.008) were upregulated in RA bone. IL17 gene expression in bone was upregulated in RA patients (p = 0.031) and correlated positively with Wnt10b (r = 0.810, p = 0.015), DKK2 (r = 0.800, p = 0.010), and RANKL/OPG ratio (r = 0.762, p = 0.028). DKK2 (p = 0.04) was significantly decreased in RA serum compared with primary OP. In conclusion, bone fragility in RA patients is induced by an unbalanced bone microenvironment and is associated with a specific gene expression pattern, namely, the upregulation of IL17 and DKK1, suggesting that the modulation of these two pathways might prevent RA systemic bone loss.

CD24: from a Hematopoietic Differentiation Antigen to a Genetic Risk Factor for Multiple Autoimmune Diseases

“…Unlike those in healthy controls, CD19 + CD24 hi CD38 hi B cells from RA patients lose the ability to inhibit the differentiation from naïve T cells into T helper 17 (Th17) cells and transform CD4 + CD25 − T cells into regulatory T (Treg) cells [116]. The Th17 and IL17 pathways have been implicated in a number of autoimmune diseases, including rheumatoid arthritis [117]. Moreover, progressive RA patients have less circulating CD19 + CD24 hi CD38 hi B cells, when compared with less progressive RA subjects or healthy controls [116].…”

Secondary osteoporosis in collagen-induced arthritis rats

“…Rheumatoid arthritis (RA) is a chronic and progressive autoimmune disease characterized by proliferative and invasive synovitis, and results in destruction of joints and erosion of cartilage and bone [1], and even disability [2] and death. It has been reported that RA is often associated with periarticular or generalized osteoporosis [3][4][5]; however, it is still controversial whether RA induces secondary osteoporosis.…”

“…A growing body of evidence indicates that the receptor activator of nuclear factor κB (RANK) ligand (RANKL) is a crucial regulator of osteoclast differentiation [10]. In addition, recent studies suggest that the Wnt signaling pathway may play a crucial role in bone destruction [2,11]. Caetano-Lopes et al [2] showed that upregulation of dickkopf 1 (DKK-1) gene expression in patients with RA causes bone fragility, but they studied only serum levels of DKK-1 in RA patients and primary osteoporosis patients.…”

“…In addition, recent studies suggest that the Wnt signaling pathway may play a crucial role in bone destruction [2,11]. Caetano-Lopes et al [2] showed that upregulation of dickkopf 1 (DKK-1) gene expression in patients with RA causes bone fragility, but they studied only serum levels of DKK-1 in RA patients and primary osteoporosis patients. Furthermore, it has been reported that cross talk between DKK-1 and osteoprotegerin (OPG) is involved in bone destruction in RA patients [12].…”

The 2014 ACR annual meeting: a bird’s eye view of autoimmunity in 2015

“…Over the past few years, clinicians have become more familiar with basic science tools such as microRNA, epigenetics, or immune cell phenotypes [182,183], while bench scientists have grown more familiar with disease activity and imaging of articular and bone damage [184,185]. As this is the case, we are convinced that this is the real added value of meetings which are capable of gathering researchers from different areas to provide a fertile field for contamination and future projects [18,[186][187][188][189][190].…”