Abstract
The immunomodulatory actions of parasitic helminth excretory-secretory (ES) products that serendipitously protect against development of chronic inflammatory disorders are well established: however, knowledge of the interaction between ES products and the host musculoskeletal system in such diseases is limited. In this study, we have focused on ES-62, a glycoprotein secreted by the rodent filarial nematode Acanthocheilonema viteae that is immunomodulatory by virtue of covalently attached phosphorylcholine (PC) moieties, and also two synthetic drug-like PC-based small molecule analogues (SMAs) that mimic ES-62’s immunomodulatory activity. We have previously shown that each of these molecules prevents development of pathology in collagen-induced arthritis (CIA), a model of the musculoskeletal disease rheumatoid arthritis (RA) and reflecting this, we now report that ES-62 and its SMAs, modify bone remodeling by altering bone marrow progenitors and thus impacting on osteoclastogenesis. Consistent with this, we find that these molecules inhibit functional osteoclast differentiation in vitro. Furthermore, this appears to be achieved by induction of anti-oxidant response gene expression, thereby resulting in reduction of the reactive oxygen species production that is necessary for the increased osteoclastogenesis witnessed in musculoskeletal diseases like RA.
Highlights
The musculoskeletal disease rheumatoid arthritis (RA) is a chronic, autoimmune inflammatory condition that results in the debilitating loss of articular bone in affected joints [1]
Our work has demonstrated that the helminth product ES-62 disrupts the IL-17 network in arthritis models without promoting a Th2 phenotype: rather, by resetting homeostatic regulatory mechanisms, ES-62 acts to interfere with a number of the key pathological processes required to drive inflammation and disease [14, 17, 22, 35]
Consistent with its ability to reset homeostatic regulation, ES-62 exhibited an ability to return the levels of hematopoietic stem cell (HSC) and OC bone marrow (BM) progenitors found in arthritic animals toward those found in healthy, “Naïve” animals and to skew the RANK/OPG/RANKL axis such that OC precursors (OCPs) would be less responsive to pathogenic signaling and result in less cathepsin K+ OCs differentiating in the inflamed joint
Summary
The musculoskeletal disease rheumatoid arthritis (RA) is a chronic, autoimmune inflammatory condition that results in the debilitating loss of articular bone in affected joints [1]. Cells associated with bone remodeling such as osteoclasts (OCs), and immune system cells including T and B lymphocytes, rely on cytokines like Receptor Activator of NF-κB Ligand (RANKL), osteoprotegerin (OPG), and pro-inflammatory mediators to control cell matu ration and pathogenic responses These events occur in the lymph node and bone marrow (BM) and ES-62 Inhibits Osteoclastogenesis drive OC differentiation at bone-remodeling sites in arthritic joints [3]. In patients with RA, synovial fibroblasts and T cells produce increased levels of RANKL and interleukin (IL)-17 compared to healthy controls, leading to the dysregulated differentiation of OCs at the articular surface, and resulting in erosion and deformation of bone [4, 5] This aberrant osteoclastogenesis contrasts with the tightly regulated interactions between OCs and their bone-forming partners, osteoblasts (OBs), that continuously act to maintain homeostatic renewal of bone [6]. Scavenging ROS with the aid of NAC in synovial fibroblasts isolated from RA patients results in their decreased RANKL production and inhibited Th17 diffe rentiation [13]
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