Background/Purpose: The complement factor H-related protein-5 (FHR-5), a member of the human factor H protein family, enhances complement activation. The influence of complement activation on bone and joint was recognized in bone fracture healing, arthritis, and osteomyelitis. Recently, FHR-5 has been linked to eye, kidney, infection, cancer and autoimmune diseases. FHR-5 was also significantly up-regulated in proteomic analysis of serum and synovial fluid for ankylosing spondylitis (AS). Hence, we aimed to evaluate whether FHR-5 exacerbates bone inflammation and ectopic formation of AS.

Methods: The study included 65 patients with AS and 25 healthy controls (HC). Collected sera were divided into three groups according to HC, two AS groups (low CRP and high CRP) based on the CRP 0.8. Human TNF, IL6, IL-17, IL-23, and FHR-5 in three groups were measured with ELISA and human FHR-5 levels were compared to TNF, IL-6, IL-17, and IL-23 levels. In addition, soluble FHR-5 proteins were administered with Curdlan-injected SKG mice 2 time for a week and monitored for 5 weeks In vivo model. Foot and ankle were evaluated by micro-CT, Hematoxylin and Eosin for histological observation, and Safranin O for cartilages. Moreover, these finding were further assessed in the AS-osteoprogenitor In vitro model.

Results: In consistent with human data, proinflammatory cytokines (TNF, IL-6, IL-17A, and IL-23) and FHR-5 were elevated in AS group compared to HC group. FHR-5 levels were not significantly correlated with proinflammatory cytokines, whereas FHR-5 levels in AS were only positively correlated with the high CRP group. Notably, treatment with soluble FHR-5 has no effect on clinical arthritis scores and thickness at hindpaw in Curdlan-injected SKG, but significantly increased the ectopic bone formation at the calcaneus and tibia bones of ankle as revealed by micro-CT image and quantification. Basal FHR-5 expression was upregulated in AS-osteoprogenitors compared to control cells. Also, treatment with FHR-5 remarkedly induced bone mineralization status of AS-osteoprogenitors during osteogenic differentiation accompanied by MMP13 expression.

Conclusion: We provide the first evidence demonstrating that FHR-5 can exacerbate pathological bone formation of AS. Therapeutic modulation of FHR-5 could be promising for future treatment of AS.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/factor-h-related-protein-5-exacerbates-pathological-bone-formation-of-ankylosing-spondylitis/