Early anti-inflammatory intervention ameliorates axial disease in the proteoglycan-induced spondylitis mouse model of ankylosing spondylitis

Abstract

BackgroundAnkylosing spondylitis (AS) is characterised by immune-mediated arthritis and osteoproliferation, ultimately leading to joint ankylosis. Whether inflammation is necessary for osteoproliferation is controversial, fuelled by the unclear efficacy of anti-inflammatory treatments on radiographic progression. In proteoglycan-induced spondylitis (PGISp), a mouse model of AS, inflammation is the prerequisite for osteoproliferation as osteoproliferation was only observed following inflammation-driven intervertebral disc (IVD) destruction. We hypothesised that early intervention with a potent anti-inflammatory therapy would protect IVD integrity and consequently alter disease progression.MethodsPGISp mice received vehicle or a combination of etanercept (ETN) plus prednisolone (PRD) therapy for 2 or 6 weeks initiated at an early disease stage. Peripheral arthritis was scored longitudinally. Spinal disease was assessed using a semi-quantitative histological scoring regimen including inflammation, joint destruction and excessive tissue formation.ResultsETN + PRD therapy significantly delayed the onset of peripheral arthritis. IVD integrity was significantly protected when treatment was commenced in early disease. Six-weeks of treatment resulted in trends towards reductions in intervertebral joint damage and excessive tissue formation. IVD score distribution was dichotomized, likely reflecting the extent of axial disease at initiation of therapy. In the sub-group of mice with high IVD destruction scores, ETN + PRD treatment significantly reduced IVD destruction severity, inflammation and bone erosion and reduced cartilage damage and excessive tissue formation.ConclusionsEarly intervention with anti-inflammatory treatment not only improved inflammatory symptoms but also ameliorated structural damage of spine in PGISp mice. This preclinical observation suggests that early anti-inflammatory intervention may slow radiographic progression in AS patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12891-017-1600-7) contains supplementary material, which is available to authorized users.

HIF1α inhibition facilitates Leflunomide-AHR-CRP signaling to attenuate bone erosion in CRP-aberrant rheumatoid arthritis

“…To date, reliable reagents specific for mouse have become available and studies suggest that serum CRP levels may be vastly underestimated 40,41 . High serum CRP levels ranging from 5 mg mL −1 to 50 mg mL −1 have been determined in different mouse models 40,42–46 , which are consistent with our results.…”

“…On the other hand, it could not be ignored that the coefficients of variation vary in large ranges for both of them 50 . We review other studies, which also show large variations of serum CRP 42–44 . In our previous work, we also demonstrate the large variations of other proteins in signaling pathways 53 .…”

Inflammation Intensity–Dependent Expression of Osteoinductive Wnt Proteins Is Critical for Ectopic New Bone Formation in Ankylosing Spondylitis

“…Previous studies have shown that some members are osteogenic. However, results have varied among studies due to differences in experimental conditions, cell types, stimulation methods and durations, and osteogenesis measurements . We screened all family members in the current culture system using different osteoprogenitor cell types to compare the osteogenic abilities of the Wnt proteins.…”

“…Four non‐transgenic models are most frequently used to study bone and joint pathology in rheumatic diseases: spontaneous arthritis in DBA/1 mice, CIA, collagen antibody–induced arthritis, and proteoglycan‐induced arthritis/PGIS. In all of these models, bone remodeling and new bone formation were found to be closely correlated to the inflammation process (). Of these models, osteophytes in the paws of DBA/1 mice and syndesmophytes leading to vertebral bony bridging in the PGIS model are most widely considered to be pathologic changes similar to new bone formation in the axial skeleton of patients with AS.…”

Aberrant upregulation of CaSR promotes pathological new bone formation in ankylosing spondylitis

“…For the PGIS model, BALB/c mice were mixed and caged in groups of 5 mice at 24 weeks of age. Cartilage PG was prepared as previous described (Mikecz et al , 1987; Tseng et al , 2016; Tseng et al , 2017). As a standard method, the first antigen injection (100 mg PG protein) was given in complete Freund’s adjuvant (Sigma, MO, USA), and the same doses of antigen were injected as second and third boosts in incomplete Freund’s adjuvant on weeks 3 and 6.…”