Session Title: Rheumatoid Arthritis: Animal Models
Session Type: Abstract Submissions (ACR)
Background/Purpose: Bone destruction in the joints of patients with rheumatoid arthritis (RA) is the result of a combination of osteoclastic bone resorption and osteoblastic bone formation. This process is not completely understood, and especially the importance of local inflammation needs further investigation. We used 3D stereological estimators to evaluate how bone formation and bone resorption are altered in autoimmune arthritis.
Methods: Twenty one 9–12-weeks-old female SKG mice were randomised to either an arthritis group or a control group. Arthritis was scored twice weekly by an observer blinded for group distribution. The fluorescent label tetracycline was injected intraperitoneally 8 days before termination of the study at the end of week 6. Right hind paws were fixed in alcohol and embedded undecalcified in methylmethacrylate. Seven-µm-thick sections were cut exhaustively according to the principles of vertical sectioning. Systematic sampling was used to obtain approximately10 levels each with 12 sections. Using newCAST stereological software, intercepts between a line grid and the tissue of interest were counted by an observer blinded for the group distribution. Osteoclast-covered bone surfaces (Oc.S) and eroded surfaces (ES) were estimated on sections stained for TRAP and mineralising surfaces (MS) were estimated on unstained sections using fluorescent microscopy. The absolute number of osteoclasts (N.Oc) was estimated using the physical fractionator. All parameters were assessed in the tarsus on the periosteal and endosteal surfaces, and the presence of adjacent inflammatory tissue was evaluated for each intersection and cell count. The relevant reference bone surface (BS) was estimated for all parameters. The results were expressed as relative values (MS/BS, ES/BS, Oc.S/BS, and N.Oc/BS).
Results: At the end of week 1 and until termination, the arthritis score was higher in arthritic animals (p<0.01). Likewise, MS/BS, ES/BS, Oc.S/BS, and N.Oc/BS were elevated in arthritic mice compared to normal mice both at the endosteal surface and the periosteal surface (p<0.001). On surfaces both adjacent to and not adjacent to inflammation in arthritic mice MS/BS were elevated on endosteal as well as periosteal surfaces compared to normal mice (p<0.001). In arthritic mice, ES/BS and Oc.S/BS were larger on endosteal as well as periosteal surfaces adjacent to inflammation compared to surfaces without inflammation (p<0.01). However, the difference between MS/BS at surfaces adjacent to and not adjacent to inflammation on either periosteal or endosteal surfaces did not reach the level of statistical significance.
Conclusion: Arthritis caused bone formation to occur on more bone surfaces, irrespectively of the adjacent tissue being inflamed. However, bone degradation was present almost exclusively on surfaces with adjacent inflammation. Therefore, arthritic bone loss is likely to be explained by an imbalance of erosion and formation of bone rather than a general down-regulation of bone formation. These findings may be important for the development of new bone targeting drugs in RA. The present study is the first to apply 3D stereological estimators to quantify bone formation and degradation in a model of RA.
K. K. Keller,
J. S. Thomsen,
J. R. Nyengaard,
E. M. Hauge,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/bone-formation-and-resorption-are-both-increased-in-autoimmune-arthritis/