Abstract
BackgroundThe aims of the present study were to determine the relationship between bone destruction and bone formation in the delayed-type hypersensitivity arthritis (DTHA) model and to evaluate the effect of receptor activator of nuclear factor κB ligand (RANKL) blockade on severity of arthritis, bone destruction, and bone formation.MethodsDTHA was induced in C57BL/6 mice. Inflammation, erosive joint damage, and new bone formation were semiquantitatively scored by histology. Osteoclast activity was assessed in vivo, and messenger RNA (mRNA) expression of mediators of bone destruction and bone formation were analyzed by mRNA deep sequencing. Serum concentrations of tartrate-resistant acid phosphatase 5b, carboxy-terminal telopeptide I (CTX-I), matrix metalloproteinase 3 (MMP3), and serum amyloid P component (SAP) were determined by enzyme-linked immunosorbent assay. Anti-RANKL monoclonal antibody treatment was initiated at the time of immunization.ResultsBone destruction (MMP3 serum levels, cathepsin B activity, and RANKL mRNA) peaked at day 3 after arthritis induction, followed by a peak in cartilage destruction and bone erosion on day 5 after arthritis induction. Periarticular bone formation was observed from day 10. Induction of new bone formation indicated by enhanced Runx2, collagen X, osteocalcin, MMP2, MMP9, and MMP13 mRNA expression was observed only between days 8 and 11. Anti-RANKL treatment resulted in a modest reduction in paw and ankle swelling and a reduction of serum levels of SAP, MMP3, and CTX-I. Destruction of the subchondral bone was significantly reduced, while no effect on bone formation was seen.ConclusionsAnti-RANKL treatment prevents joint destruction but does not prevent new bone formation in the DTHA model. Thus, although occurring sequentially during the course of DTHA, bone destruction and bone formation are apparently not linked in this model.
Highlights
The aims of the present study were to determine the relationship between bone destruction and bone formation in the delayed-type hypersensitivity arthritis (DTHA) model and to evaluate the effect of receptor activator of nuclear factor κB ligand (RANKL) blockade on severity of arthritis, bone destruction, and bone formation
We investigated the spatiotemporal occurrence of bone destruction and new bone formation by histological analysis, by performing an expression analysis of genes involved in tissue destruction and bone formation, and by analysis of the effect of preventive receptor activator of nuclear factor κB ligand (RANKL) blockade
Pathology in DTHA is characterized by early development of periarticular and subchondral pannus tissue To examine tissue pathology in the DTHA model, we induced DTHA as described previously [15] and performed an extensive histopathological analysis with the purpose of assessing inflammation, pannus formation, tissue destruction, and new bone formation
Summary
The aims of the present study were to determine the relationship between bone destruction and bone formation in the delayed-type hypersensitivity arthritis (DTHA) model and to evaluate the effect of receptor activator of nuclear factor κB ligand (RANKL) blockade on severity of arthritis, bone destruction, and bone formation. In axial SpA, chronic inflammation predominantly affects the sacroiliac joints and vertebral bodies [3] This is accompanied by local bone erosion and more prominent new bone formation, leading to joint ankylosis and syndesmophyte development [4]. Histological analysis of facet joints from patients with ankylosing spondylitis (AS), the progressed form of axial SpA, showed erosive damage of the subchondral bone from the bone marrow side. This damage is driven by osteoclasts located at the leading edge of a subchondral fibroblast-rich granulation tissue [10], which invades the subchondral bone. In mouse models of SpA, in the DBA/1 model, where grouped caging of male DBA/1 mice leads to development of ankylosing enthesitis [13], destruction and bone formation do not seem to be linked, because inhibition of osteoclast function does not prevent new bone formation [14]
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