Relationship between inflammation, bone destruction, and osteoproliferation in the HLA–B27/human β₂‐microglobulin–transgenic rat model of spondylarthritis

Abstract

Objective Inhibition of inflammation and destruction but not osteoproliferation in spondyloarthritis (SpA) patients treated with anti-TNF raises the question of how these three processes are interrelated. This study aimed to analyze this relationship in a SpA rat model. Methods Histological spine and joint samples of HLA-B27/Huβ2m transgenic rats were analyzed for signs of spondylitis and destructive arthritis and semi-quantitatively scored as mild, moderate or severe inflammation. Results In spondylitis, mild inflamed sections displayed lymphocyte infiltration in connective tissue adjacent to the junction of the annulus fibrosus and vertebral bone but not at the enthesis. Moderate inflamed tissue samples contained osteoclasts eroding bone outside the cartilage endplate. In severe inflammation, the cartilage endplate and underlying bone marrow were also affected. End-stage disease was characterized by complete destruction of the intervertebral disc and vertebrae, with ongoing infiltration. Osteoproliferation was not observed in samples with no or mild inflammation, but was present at the edge of the vertebrae in moderate inflammation and persisted during severe inflammation and end-stage destruction. Osteoproliferation occurred at the border of inflammation, at a distance from bone destruction. A strong correlation between the extent of inflammation, destruction and osteoproliferation was observed. Arthritis displayed a similar pattern of synovial inflammation associated with bone destruction, and simultaneous but topographically distinct osteoproliferation starting from the periosteum. Conclusion Spondyloarthritis in HLA-B27/Huβ2m tg rats is characterized by destructive inflammatory pannus tissue rather than by enthesitis or osteitis. Destruction and osteoproliferation occur simultaneously but at distinct sites in joints with moderate to severe inflammation.

Inflammatory pathways in spondyloarthritis

“…However, this hypothesis does not fit with animal models demonstrating that complete inhibition of inflammation-driven bone destruction does not inhibit osteoproliferation, questioning the concept of reparative bone formation (Lories et al, 2008;Schett et al, 2009). Moreover, detailed analysis of the pathology of HLA-B27 transgenic rats, a spontaneous model of human SpA, shows that osteoproliferation occurs simultaneously with inflammation and destruction (Van Duivenvoorde et al, 2012). Finally, long-term clinical observations indicate that TNF blockade in established AS does not lead to new bone formation (Baraliakos et al, 2013).…”

Inflammation-driven bone formation in ankylosing spondylitis: characterisation of the proteoglycan-induced spondylitis mouse model

“…The entheseal proliferation and inflammatory infiltrate were minor in this model and treatment with glucocorticoids [156], but not etanercept [157], did ameliorate inflammation somewhat but had no effect on the ankylosis. In a longitudinal study in HLA-B27/h2m transgenic rats, osteoproliferation was found external to the joint space separate from inflammatory infiltrates [139]. However, osteoproliferation and inflammation in HLA-B27/h2m transgenic rats were presented simultaneously suggesting distinct but parallel processes.…”

“…The initial symptom is gastrointestinal inflammation followed by other inflammatory features present in SpA, such as peripheral arthritis, spondylitis, enthesitis and psoriasis [138]. In addition to inflammation, chondrocyte proliferation and syndesmophyte formation, were observed in the peripheral joints and spine [139]. The copy number of HLA-B27 and h2m molecules has a threshold effect on the susceptibility to spontaneous arthritis/spondylitis.…”

“…Severe inflammation, bone erosion and chondroproliferation were observed simultaneously at affected sites [139]. The chondrocyte proliferation and hypertrophy have been suggested to be the result of activation of the BMP/Smad pathway [114].…”

“…Enthesitis and osteoproliferation have also been reported in DBA/1 mice [153], HLA-B27/h2m transgenic rats [139] and curdlan-treated SKG mice [160]. However, the relationship between the processes is not well-defined.…”