Cargando…

Inflammation-driven bone formation in a mouse model of ankylosing spondylitis: sequential not parallel processes

BACKGROUND: Ankylosing spondylitis (AS) is an immune-mediated arthritis particularly targeting the spine and pelvis and is characterised by inflammation, osteoproliferation and frequently ankylosis. Current treatments that predominately target inflammatory pathways have disappointing efficacy in slo...

Descripción completa

Detalles Bibliográficos
Autores principales: Tseng, Hsu-Wen, Pitt, Miranda E., Glant, Tibor T., McRae, Allan F., Kenna, Tony J., Brown, Matthew A., Pettit, Allison R., Thomas, Gethin P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4734853/
https://www.ncbi.nlm.nih.gov/pubmed/26831337
http://dx.doi.org/10.1186/s13075-015-0805-0
_version_ 1782412986075316224
author Tseng, Hsu-Wen
Pitt, Miranda E.
Glant, Tibor T.
McRae, Allan F.
Kenna, Tony J.
Brown, Matthew A.
Pettit, Allison R.
Thomas, Gethin P.
author_facet Tseng, Hsu-Wen
Pitt, Miranda E.
Glant, Tibor T.
McRae, Allan F.
Kenna, Tony J.
Brown, Matthew A.
Pettit, Allison R.
Thomas, Gethin P.
author_sort Tseng, Hsu-Wen
collection PubMed
description BACKGROUND: Ankylosing spondylitis (AS) is an immune-mediated arthritis particularly targeting the spine and pelvis and is characterised by inflammation, osteoproliferation and frequently ankylosis. Current treatments that predominately target inflammatory pathways have disappointing efficacy in slowing disease progression. Thus, a better understanding of the causal association and pathological progression from inflammation to bone formation, particularly whether inflammation directly initiates osteoproliferation, is required. METHODS: The proteoglycan-induced spondylitis (PGISp) mouse model of AS was used to histopathologically map the progressive axial disease events, assess molecular changes during disease progression and define disease progression using unbiased clustering of semi-quantitative histology. PGISp mice were followed over a 24-week time course. Spinal disease was assessed using a novel semi-quantitative histological scoring system that independently evaluated the breadth of pathological features associated with PGISp axial disease, including inflammation, joint destruction and excessive tissue formation (osteoproliferation). Matrix components were identified using immunohistochemistry. RESULTS: Disease initiated with inflammation at the periphery of the intervertebral disc (IVD) adjacent to the longitudinal ligament, reminiscent of enthesitis, and was associated with upregulated tumor necrosis factor and metalloproteinases. After a lag phase, established inflammation was temporospatially associated with destruction of IVDs, cartilage and bone. At later time points, advanced disease was characterised by substantially reduced inflammation, excessive tissue formation and ectopic chondrocyte expansion. These distinct features differentiated affected mice into early, intermediate and advanced disease stages. Excessive tissue formation was observed in vertebral joints only if the IVD was destroyed as a consequence of the early inflammation. Ectopic excessive tissue was predominantly chondroidal with chondrocyte-like cells embedded within collagen type II- and X-rich matrix. This corresponded with upregulation of mRNA for cartilage markers Col2a1, sox9 and Comp. Osteophytes, though infrequent, were more prevalent in later disease. CONCLUSIONS: The inflammation-driven IVD destruction was shown to be a prerequisite for axial disease progression to osteoproliferation in the PGISp mouse. Osteoproliferation led to vertebral body deformity and fusion but was never seen concurrent with persistent inflammation, suggesting a sequential process. The findings support that early intervention with anti-inflammatory therapies will be needed to limit destructive processes and consequently prevent progression of AS. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13075-015-0805-0) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-4734853
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-47348532016-02-02 Inflammation-driven bone formation in a mouse model of ankylosing spondylitis: sequential not parallel processes Tseng, Hsu-Wen Pitt, Miranda E. Glant, Tibor T. McRae, Allan F. Kenna, Tony J. Brown, Matthew A. Pettit, Allison R. Thomas, Gethin P. Arthritis Res Ther Research Article BACKGROUND: Ankylosing spondylitis (AS) is an immune-mediated arthritis particularly targeting the spine and pelvis and is characterised by inflammation, osteoproliferation and frequently ankylosis. Current treatments that predominately target inflammatory pathways have disappointing efficacy in slowing disease progression. Thus, a better understanding of the causal association and pathological progression from inflammation to bone formation, particularly whether inflammation directly initiates osteoproliferation, is required. METHODS: The proteoglycan-induced spondylitis (PGISp) mouse model of AS was used to histopathologically map the progressive axial disease events, assess molecular changes during disease progression and define disease progression using unbiased clustering of semi-quantitative histology. PGISp mice were followed over a 24-week time course. Spinal disease was assessed using a novel semi-quantitative histological scoring system that independently evaluated the breadth of pathological features associated with PGISp axial disease, including inflammation, joint destruction and excessive tissue formation (osteoproliferation). Matrix components were identified using immunohistochemistry. RESULTS: Disease initiated with inflammation at the periphery of the intervertebral disc (IVD) adjacent to the longitudinal ligament, reminiscent of enthesitis, and was associated with upregulated tumor necrosis factor and metalloproteinases. After a lag phase, established inflammation was temporospatially associated with destruction of IVDs, cartilage and bone. At later time points, advanced disease was characterised by substantially reduced inflammation, excessive tissue formation and ectopic chondrocyte expansion. These distinct features differentiated affected mice into early, intermediate and advanced disease stages. Excessive tissue formation was observed in vertebral joints only if the IVD was destroyed as a consequence of the early inflammation. Ectopic excessive tissue was predominantly chondroidal with chondrocyte-like cells embedded within collagen type II- and X-rich matrix. This corresponded with upregulation of mRNA for cartilage markers Col2a1, sox9 and Comp. Osteophytes, though infrequent, were more prevalent in later disease. CONCLUSIONS: The inflammation-driven IVD destruction was shown to be a prerequisite for axial disease progression to osteoproliferation in the PGISp mouse. Osteoproliferation led to vertebral body deformity and fusion but was never seen concurrent with persistent inflammation, suggesting a sequential process. The findings support that early intervention with anti-inflammatory therapies will be needed to limit destructive processes and consequently prevent progression of AS. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13075-015-0805-0) contains supplementary material, which is available to authorized users. BioMed Central 2016-01-29 2016 /pmc/articles/PMC4734853/ /pubmed/26831337 http://dx.doi.org/10.1186/s13075-015-0805-0 Text en © Tseng et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Tseng, Hsu-Wen
Pitt, Miranda E.
Glant, Tibor T.
McRae, Allan F.
Kenna, Tony J.
Brown, Matthew A.
Pettit, Allison R.
Thomas, Gethin P.
Inflammation-driven bone formation in a mouse model of ankylosing spondylitis: sequential not parallel processes
title Inflammation-driven bone formation in a mouse model of ankylosing spondylitis: sequential not parallel processes
title_full Inflammation-driven bone formation in a mouse model of ankylosing spondylitis: sequential not parallel processes
title_fullStr Inflammation-driven bone formation in a mouse model of ankylosing spondylitis: sequential not parallel processes
title_full_unstemmed Inflammation-driven bone formation in a mouse model of ankylosing spondylitis: sequential not parallel processes
title_short Inflammation-driven bone formation in a mouse model of ankylosing spondylitis: sequential not parallel processes
title_sort inflammation-driven bone formation in a mouse model of ankylosing spondylitis: sequential not parallel processes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4734853/
https://www.ncbi.nlm.nih.gov/pubmed/26831337
http://dx.doi.org/10.1186/s13075-015-0805-0
work_keys_str_mv AT tsenghsuwen inflammationdrivenboneformationinamousemodelofankylosingspondylitissequentialnotparallelprocesses
AT pittmirandae inflammationdrivenboneformationinamousemodelofankylosingspondylitissequentialnotparallelprocesses
AT glanttibort inflammationdrivenboneformationinamousemodelofankylosingspondylitissequentialnotparallelprocesses
AT mcraeallanf inflammationdrivenboneformationinamousemodelofankylosingspondylitissequentialnotparallelprocesses
AT kennatonyj inflammationdrivenboneformationinamousemodelofankylosingspondylitissequentialnotparallelprocesses
AT brownmatthewa inflammationdrivenboneformationinamousemodelofankylosingspondylitissequentialnotparallelprocesses
AT pettitallisonr inflammationdrivenboneformationinamousemodelofankylosingspondylitissequentialnotparallelprocesses
AT thomasgethinp inflammationdrivenboneformationinamousemodelofankylosingspondylitissequentialnotparallelprocesses