Abstract
IntroductionPatients with chronic inflammatory diseases have increased bone loss and bone fragility and are at increased risk of fracture. Although anti-resorptive drugs are effective in blocking inflammation-induced bone loss, they are less effective at rebuilding bone. We have previously shown that treatment with sclerostin antibody (Scl-AbI) builds bone and can prevent or restore bone loss in a murine model of inflammatory bowel disease. In this study, we tested the effect of Scl-AbI in a murine model of rheumatoid arthritis (the collagen-induced arthritis model, CIA). We hypothesised that sclerostin blockade can protect and restore bone both locally and systemically without affecting progression of inflammation.MethodsCIA was induced in male DBA/1 mice, which were treated with either PBS or Scl-AbI (10 mg/kg, weekly) prophylactically for 55 days or therapeutically for 21 days (starting 14 days post onset of arthritis). Systemic inflammation was assessed by measuring the serum concentration of anti-CII IgG1, IgG2a and IgG2b by ELISA. Changes in bone mass and structure, either at sites remote from the joints or at periarticular sites, were measured using DEXA and microCT. Bone focal erosion was assessed in microCT scans of ankle and knee joints.ResultsCirculating anti-CII immunoglobulins were significantly elevated in mice with CIA and there were no significant differences in the levels of anti-CII immunoglobulins in mice treated with PBS or Scl-ABI. Prophylactic Scl-AbI treatment prevented the decrease in whole body bone mineral density (BMD) and in the bone volume fraction at axial (vertebral body) and appendicular (tibial proximal metaphysis trabecular and mid-diaphysis cortical bone) sites seen in PBS-treated CIA mice, but did not prevent the formation of focal bone erosions on the periarticular bone in the knee and ankle joints. In the therapeutic study, Scl-AbI restored BMD and bone volume fraction at all assessed sites but was unable to repair focal erosions.ConclusionsSclerostin blockade prevented or reversed the decrease in axial and appendicular bone mass in the murine model of rheumatoid arthritis, but did not affect systemic inflammation and was unable to prevent or repair local focal erosion.
Highlights
Patients with chronic inflammatory diseases have increased bone loss and bone fragility and are at increased risk of fracture
Prophylactic sclerostin antibody (Scl-AbI) treatment prevented the decrease in whole body bone mineral density (BMD) and in the bone volume fraction at axial and appendicular sites seen in phosphate-buffered saline (PBS)-treated collagen-induced arthritis (CIA) mice, but did not prevent the formation of focal bone erosions on the periarticular bone in the knee and ankle joints
Scl-AbI treatment had no significant effect on the concentration of anti-chicken type II collagen (CII) immunoglobulins (IgG1, IgG2a or IgG2b), which were all significantly elevated in PBStreated arthritic mice compared with healthy controls (Figure 1C, D, E)
Summary
Patients with chronic inflammatory diseases have increased bone loss and bone fragility and are at increased risk of fracture. Patients with chronic inflammatory diseases - for example rheumatoid arthritis (RA), systemic lupus erythematosus, inflammatory bowel disease (IBD), celiac disease, cystic fibrosis and chronic obstructive pulmonary disease - have increased bone fragility and are at an increased risk of pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), or interferon-gamma, which have all been shown to modulate osteoclastogenesis [1]. Other cytokines such as receptor activator of nuclear factor kappa B (RANK), its ligand, RANKL, and osteoprotegerin (OPG) are critically involved in the pathophysiology of inflammatory bone loss [3]. In early RA, radiographic demineralisation appears around inflamed joints, while bone erosions appear later [4]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
