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Intracellular apoptotic pathways: a potential target for reducing joint damage in rheumatoid arthritis

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Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that results in both local and systemic bone erosion, causing significant joint deformities and functional disability. The increased number of synovial fibroblasts, inflammatory cells and osteoclasts in RA is associated with reduced apoptosis in these cells. The ability to modulate the cell proliferation or death (particularly apoptosis) is recognised for its immense therapeutic potential. Identifying new therapeutics to assist in stimulating apoptosis within the synovial joints therefore may be beneficial in reducing inflammation and bone loss in RA patients. In this review, the roles of anti-apoptotic proteins that are upregulated in RA synovial joints will be discussed in relation to their actions on bone destruction and inflammation. Evidence recently published suggests that intracellular apoptotic inhibitory molecules can be targeted by current or new therapeutics to reduce joint damage in RA. However, the therapeutics that target these molecules are yet to reach clinical trial stages. Even so it is evident that understanding the upregulation of anti-apoptotic molecules in RA is required to improve treatments currently available for RA patients.

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Abbreviations

AIA:

Adjuvant-induced arthritis

AIF:

Apoptosis-inducing factor

BIR:

Baculovirus inhibitor of apoptosis protein repeats

CAIA:

Collagen antibody-induced arthritis

DISC:

Death-inducing signalling complex

DMARDs:

Disease-modifying anti-rheumatic drugs

FADD:

Fas-associated death domain

FLS:

Fibroblast-like synoviocytes

FLIP:

FLICE-like inhibitory protein

IL:

Interleukins

IAP:

Inhibitor of apoptosis proteins

NF-κB:

Nuclear factor-kappa B

PAPR:

Poly ADP-ribose polymerase

RA:

Rheumatoid arthritis

RANK:

Receptor activator of NF-κB

RANKL:

Receptor activator of NF-κB ligand

RIP:

Receptor-interacting protein

SMAC:

Second mitochondrial activator of caspases

TRAIL:

Tumour necrosis factor-related apoptosis-inducing ligand

TRAP:

Tartrate-resistant acid phosphatase

TNF-α:

Tumour necrosis factor alpha

TUNEL:

Transferase dUTP nick end labelling

TRADD:

TNF receptor type-1 associated death domain

XIAP:

X-linked inhibitor of apoptosis protein

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Acknowledgements

We would like to acknowledge the professional work of Mr. Tavik Morgenstern; Learning and Teaching Officer, University of Adelaide, for his assistance in the preparation of the figure. BW was supported by an Australian Government Research Training Program Scholarship.

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  1. Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia

    Bonnie Williams, Anak Dharmapatni & Tania Crotti

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  1. Bonnie Williams
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BW carried out the literature review, preparing and writing the manuscript with supervision from TC and AD. TC and AD contributed to the writing of the manuscript, discussing the literature and presentation of figures. All authors read and approved the final manuscript.

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Correspondence to Bonnie Williams.

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Communicated by Yoshiya Tanaka.

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Williams, B., Dharmapatni, A. & Crotti, T. Intracellular apoptotic pathways: a potential target for reducing joint damage in rheumatoid arthritis. Inflamm. Res. 67, 219–231 (2018). https://doi.org/10.1007/s00011-017-1116-5

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  • DOI: https://doi.org/10.1007/s00011-017-1116-5

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