Session Title: Rheumatoid Arthritis - Animal Models II
Session Type: Abstract Submissions (ACR)
Background/Purpose: The Wnt pathway plays an important role in bone formation and regeneration. This pathway is regulated by several soluble inhibitors such as Dickkopf-1 (DKK-1) and sclerostin. However, it is not fully understood how development of arthritis affects DKK-1 and sclerostin production, or if levels of DKK-1 and sclerostin are improved by blockade of interleukin-6 (IL-6) or tumor necrosis factor-α (TNF-α). The purpose of this study was to examine DKK-1 and sclerostin production in inflammatory arthritis and how it is affected by blockade of IL-6 or TNF-α, using a mouse model of collagen-induced arthritis (CIA).
Methods: CIA in DBA/1J mice was triggered by intradermal injection of bovine type II collagen on Days 0 and 21. Mice were injected intraperitoneally with either anti-mouse IL-6 receptor antibody (MR16-1) on Days 0 and 21 or with TNF receptor-Fc (TNFR-Fc) 3 times per week from the first immunization. Serum was sampled on Days 14 (before swelling), 35 (peak of swelling), and 56 (after swelling subsides). Serum Wnt signalling inhibitors (DKK-1 and sclerostin) were measured by ELISA. Hind limb bones (periarticular bone) and the lumbar spine (systemic bone) were excised on Day 56. Bone volume (BV/TV) of the hind limb (cuboid bone) and the lumbar spine (trabecular bone of L6) was analysed by micro-computed tomography (μCT).
Results: In CIA mice, BV/TV of the hind limb and lumbar spine on Day 56 were significantly decreased to 72.6% (p<0.0001) and 62.1% (p<0.0001) of the respective values in non-immunized mice. MR16-1 and TNFR-Fc each significantly suppressed the development of arthritis (p<0.001 and p<0.05) and bone loss in the hind limb (p<0.0001 and p<0.01) compared with untreated CIA mice. On the other hand, bone loss in the lumbar spine was significantly suppressed by only MR16-1 (p<0.0001) and not by TNFR-Fc (p=0.367). On Days 14, 35, and 56, DKK-1 levels were significantly higher in CIA mice than in non-immunized mice (p<0.0001). Sclerostin levels were significantly lower on Days 14 and 35 in CIA mice than in non-immunized mice (p<0.0001). In MR16-1-treated CIA mice, DKK-1 was significantly lower than in untreated CIA mice on Days 35 and 56 (p<0.0001 and p<0.01), and sclerostin was significantly higher on Days 14 and 35 (p<0.0001). In TNFR-Fc-treated CIA mice, on the other hand, although DKK-1 on Day 35 was as significantly decreased as it was in MR16-1-treated mice (p<0.0001), sclerostin levels on Day 35 were similar to those of untreated CIA mice (p=0.988).
Conclusion: The high DKK-1 level in CIA mice was suppressed by blockade of not only TNF-α but also IL-6. This result indicates one mechanism through which blockade of TNF-α and IL-6 suppresses periarticular bone loss. However, DKK-1 might not affect systemic bone loss because TNFR-Fc treatment did not suppress bone loss in the lumbar spine. On the other hand, although sclerostin levels were significantly lower in CIA mice than in non-immunized mice, sclerostin levels were normalized only by blockade of IL-6. Our findings suggested that anti-IL-6 receptor antibody would have a beneficial effect on both periarticular and systemic bone loss by normalizing the Wnt pathway in inflammatory arthritis.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-il-6-receptor-antibody-normalizes-both-dkk-1-and-sclerostin-as-wnt-inhibitors-in-a-mouse-model-of-collagen-induced-arthritis/