Additive bone‐protective effects of anabolic treatment when used in conjunction with RANKL and tumor necrosis factor inhibition in two rat arthritis models

Abstract

Objective. To investigate whether the bonepreserving effects of a RANKL antagonist or a tumor necrosis factor (TNF) antagonist could be further improved by the addition of a bone anabolic agent in inflammatory arthritis.Methods. Lewis rats with either adjuvant-induced arthritis (AIA) or collagen-induced arthritis (CIA) were treated for 10 days with PEGylated soluble tumor necrosis factor receptor type I (PEG sTNFRI), interleukin-1 receptor antagonist (IL-1Ra), osteoprotegerin (OPG), parathyroid hormone (PTH), or combinations of these agents starting on day 4 after disease onset. Treatment effects were assessed clinically, radiologically, and histologically, and by morphometry for the extent of paw swelling, bone erosive changes, and synovial inflammation.Results. Paw swelling and synovial inflammation were significantly inhibited by PEG sTNFRI in AIA and CIA, and by IL-1Ra in CIA. OPG and PTH had no significant effect on these parameters. Analysis of bone erosion revealed a significant bone-sparing effect of monotherapy with PEG sTNFRI or OPG in both models, whereas IL-1Ra was only effective in CIA. PTH treatment alone did not show a bone-protective effect in either model. With the combination of PEG sTNFRI and PTH, erosion scores (؊74% in AIA and ؊61% in CIA versus controls) were significantly lower than those elicited by PEG sTNFRI alone (؊41% and ؊29%, respectively, versus controls). Similar results were also obtained with the combination of OPG and PTH (؊88% in AIA and ؊73% in CIA, compared with ؊70% and ؊55%, respectively, with OPG monotherapy). Coadministration of IL-1Ra and PTH had no synergistic bonesparing effect. Morphometric analysis revealed that the addition of PTH to PEG sTNFRI or OPG resulted in higher bone volume and higher osteoblast numbers in both AIA and CIA.Conclusion. The bone-protective effects resulting from RANKL or TNF antagonism can be further improved by the addition of a bone anabolic agent.

The Evolving Systemic and Local Biomarker Milieu at Different Stages of Disease Progression in Rat Adjuvant-Induced Arthritis

“…Systemic TNFα augments the process by releasing osteogenic precursors from the bone marrow and by 'priming' them to respond to RANKL [58,59]. This interpretation is further supported as a general principle for pro-arthritic signaling molecules by our prior demonstration that different systemic and local concentrations of RANKL (a TNF superfamily member that is an essential mediator of bone erosions) were strongly correlated with the induction of divergent degrees of systemic and local osteopenia in rats with AIA starting as early as the day of disease onset [24,42]. Secondly, the nature of the inflammatory changes differed in regional lymph nodes (inguinal, popliteal) relative to more distant lymphoid tissues (mesenteric lymph nodes, spleen).…”

“…Rat AIA is a well-characterized model for assessing arthritis mechanisms [10,11,23,24,34,45,46]. For this study, disease was investigated by taking clinical measurements as well as fluid (serum) and tissue (hind paws, femur, lymphoid organs) samples on 14 occasions: before onset (−5, −3, or −1 days), at onset (indicated by hind paw swelling and ambulatory difficulties), and during clinical arthritis progression (+1, +2, +3, +4, +5, +7, +10, +14, +20, and +27 days after onset).…”

“…However, while inhibition of IL-1, TNFα, or both yields a significant anti-inflammatory effect in rats with AIA, residual disease persists [11,23,24]. Such lingering inflammation might be related to submaximal inhibition of the intended targets or, alternatively, to potential contributions by other pro-inflammatory cytokines (e.g., IL-6, IL-12, IL-15, IL-17, IL-18 [25,26]) and chemokines (e.g., chemokine (C-C motif) ligand 2 (CCL2) [formerly monocyte chemotactic protein-1 [27]], CXC chemokine ligand 8 (CXCL8) [formerly IL-8 [28]]).…”

The RANK/RANKL/osteoprotegerin system in rheumatoid arthritis: New insights from animal models

“…In a recent study of adjuvant-induced arthritis and collagen-induced arthritis in Lewis rats, TNF inhibition resulted in a strong decrease of inflammation and bone erosion in both models (63). In contrast, IL-1Ra was effective only in collagen-induced arthritis, and OPG had protective effects against bone erosion, accompanied by higher numbers of osteoblasts and increased bone volume, but was not protective against inflammation.…”

Role of NF-κB in the skeleton

“…Bone surfaces adjacent to inflammation have decreased bone formation rates, associated with lower expression of markers of mature OBs [65,66]. Given the inhibitory effects of TNFα on OB differentiation discussed above, it is likely that classical NF-κB activation is involved in the decreased bone formation.…”