Background/Purpose:

Transition from an initial inflammatory phase to the disabling osteoproliferative phase in ankylosing spondylitis (AS) is very poorly understood. Elucidation of the mechanisms underlying this disease progression would identify new therapeutic targets and strategies.

The proteoglycan induced spondylitis (PGISp) mouse mirrors human AS disease progression with an initial inflammatory insult resulting in excessive osteoproliferation and frequently joint fusion. We therefore sought to model human AS progression by extensively characterizing the morphological, cellular and molecular changes over a time course of disease in the PGISp mouse

Methods:

Spine and spleen cells from PGISp and control mice were analysed over a 6 month timecourse. The histological features were described using a novel scoring regime including many features seen in human AS, such as inflammation, disc destruction, bone erosion, excess tissue formation (mesenchymal tissue expansion or fibrocartilage formation) around IVDs as well as ectopic tissue formation in the longitudinal ligament. Immunohistochemistry for collagens type I, II and X was used to delineate the nature of the excessive tissue formation seen in this model. Key factors involved both at the joint and systemic levels were analyzed using FACS and qPCR.

Results:

Initial inflammation at the periphery of the discs was seen from week 6 which corresponded with an upregulation in expression of inflammatory markers such as TNFa, MMP3 and MMP13. Inflammation progressed over the next 4 weeks with massive inflammatory cell infiltration, disc destruction and erosion of bone and growth plate cartilage. A switch to an “anabolic” phase was then evident with upregulation of collagen II and X, and a corresponding decrease in inflammatory/catabolic genes. An extensive fibrocartilaginous matrix is laid down (excessive tissue formation) by large numbers of chondrocytes.  One key feature of severely affected vertebrae is the appearance of ectopic chondrocytes laying down a cartilaginous matrix between the vertebral joints possibly corresponding to entheseal junctions. Such a feature potentially supports a role for endochondral ossification in the disease progression in this model.

Conclusion:

The PGISp mouse model displays many features of AS. Of key interest is the initial inflammation giving way to extensive tissue formation. The presence of ectopic chondrocytes indicative of endochondral ossification at the entheses is a key insight into the disease process that can be translated to the human condition.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/endochondral-bone-formation-and-advanced-enthesitis-are-key-features-of-proteoglycan-induced-spondylitis-mouse-model-of-ankylosing-spondylitis/