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. and Thomas, Gethin P. (2016) Inflammation-driven bone formation in a mouse model of ankylosing spondylitis: sequential not parallel processes. Arthritis Research and Therapy, 18 1: . doi:10.1186/s13075-015-0805-0

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.
Title Inflammation-driven bone formation in a mouse model of ankylosing spondylitis: sequential not parallel processes
Journal name Arthritis Research and Therapy   Check publisher's open access policy
ISSN 1478-6362
Publication date 2016-01-29
Sub-type Article (original research)
DOI 10.1186/s13075-015-0805-0
Open Access Status DOI
Volume 18
Issue 1
Total pages 12
Place of publication London, United Kingdom
Publisher BioMed Central
Collection year 2017
Language eng
Formatted abstract
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.

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.

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.

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.
Keyword Ankylosing spondylitis
Chondroidal bone formation
Intervertebral disc destruction
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ
Additional Notes Article number 35

Document type: Journal Article
Sub-type: Article (original research)
Collections: Mater Research Institute-UQ (MRI-UQ)
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