Protection against arthritis by the parasitic worm product ES-62, and its drug-like small molecule analogues, is associated with inhibition of osteoclastogenesis

Doonan, J., Lumb, F. E., Pineda, M. A., Tarafdar, A., Crowe, J., Khan, A. M., Suckling, C. J., Harnett, M. M. and Harnett, W. (2018) Protection against arthritis by the parasitic worm product ES-62, and its drug-like small molecule analogues, is associated with inhibition of osteoclastogenesis. Frontiers in Immunology, 9, 1016. (doi:10.3389/fimmu.2018.01016) (PMID:29867986) (PMCID:PMC5967578)

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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.

Item Type:Articles
Keywords:Rheumatoid arthritis, immunomodulation, osteoclast, Es-62, parasitic worm.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Khan, Aneesah and Harnett, Professor Margaret and Tarafdar, Ms Anuradha and Lumb, Miss Felicity and Crowe, Dr Jenny and Pineda, Dr Miguel and Harnett, Professor William and Doonan, Dr James
Authors: Doonan, J., Lumb, F. E., Pineda, M. A., Tarafdar, A., Crowe, J., Khan, A. M., Suckling, C. J., Harnett, M. M., and Harnett, W.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Frontiers in Immunology
Publisher:Frontiers
ISSN:1664-3224
ISSN (Online):1664-3224
Copyright Holders:Copyright © 2018 Doonan, Lumb, Pineda, Tarafdar, Crowe, Khan, Suckling, Harnett and Harnett
First Published:First published in Frontiers in Immunology 9: 1016
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
703241MIMIC - Do parasitic worms and their secreted immunomodulators protect against musculosketal disease by impacting on the host microbiome?Margaret HarnettArthritis Research UK (ARTRESUK)21133III -IMMUNOLOGY
692661Can studying the mechanism of action of the parasitic worm-derived immunomodulator ES-62, inform on how to slow ageing and improve healthspan?Margaret HarnettBiotechnology and Biological Sciences Research Council (BBSRC)BB/M029727/1III -IMMUNOLOGY