Background Patients with rheumatoid arthritis (RA) have a high risk of osteoporosis and osteoporotic fracture. In primary osteoporosis (either high bone turnover osteoporosis [type I] or low bone turnover osteoporosis [type II]), bone loss is induced by an imbalance of bone metabolism: bone resorption dominates bone formation. However, it is not fully understood how RA affects bone metabolism or if bone metabolism is improved by blockade of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α).
Objectives We aimed to examine change in the balance between bone resorption markers and bone formation markers in inflammation, 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 day 0 and 21. Mice were injected with anti-mouse IL-6 receptor antibody (MR16-1) intraperitoneally on days 0 and 21. On the other hand, TNF receptor-Fc (TNFR-Fc) was given intraperitoneally 3 times per week from the first immunization. Serum and urine were sampled on days 14 (before swelling), 35 (peak of swelling), and 54 (after swelling subsides). Urinary bone resorption markers (DPD: deoxypyridinoline, CTX: collagen type 1 cross-linked C-telopeptide) and serum bone formation markers (P1NP: procollagen type 1 N-terminal propeptide, OC: osteocalcin) were measured by ELISA. The lumbar spine was excised on day 56, and trabecular bone volume (BV/TV) was analysed by micro-computed tomography (μCT).
Results In CIA mice, lumbar spine BV/TV on day 56 had significantly declined by 62.1% compared with non-immunized mice. Both MR16-1 and TNFR-Fc significantly suppressed development of arthritis compared with untreated CIA mice. In MR16-1-treated mice, lumbar spine BV/TV was significantly increased to 1.44 times that of untreated CIA mice; TNFR-Fc also increased BV/TV (1.13 times), but not significantly. On days 35 and 54, CTX and DPD levels were significantly higher in CIA mice than in non-immunized mice. OC level in CIA mice was significantly lowered on day 14. On day 35, OC had recovered to the level in non-immunized mice; however, P1NP was significantly lower. In MR16-1-treated mice, bone resorption markers were significantly lower on days 35 (CTX) and 54 (CTX and DPD) than in untreated CIA mice, and bone formation markers were significantly higher on days 14 (P1NP) and 35 (P1NP and OC). Moreover, bone formation markers were higher on day 35 than in non-immunized mice. In TNFR-Fc-treated mice, on the other hand, although bone resorption markers on days 35 (CTX) and 54 (DPD) were significantly decreased, bone formation marker levels were similar to those of untreated CIA mice.
Conclusions We demonstrated that CIA induced severe bone loss by an imbalance of bone metabolism, not only increasing bone resorption but also suppressing bone formation. Moreover, our results indicated that both IL-6 and TNF play an important role in increasing bone resorption, but that only IL-6 played a crucial role in decreasing bone formation. Our findings provide evidence that anti-IL-6 receptor antibody would have a beneficial effect on systemic osteoporosis in RA patients.
Disclosure of Interest None Declared