Tenosynovitis and osteoclast formation as the initial preclinical changes in a murine model of inflammatory arthritis.
OBJECTIVE
To determine the nature of the initial changes of joint inflammation occurring before, at the time of, and shortly after onset of clinically apparent arthritis.


METHODS
Human tumor necrosis factor (TNF)-transgenic mice were assessed for clinical, histologic, immunophenotypic, serologic, and molecular changes at the preclinical phase of arthritis, at the onset of disease, and at the stage of early clinical disease. In addition, the effects of a genetic osteoclast deficiency and pharmacologic inhibition of TNF were studied in these initial phases of disease.


RESULTS
Initial articular changes were observed even before the start of clinical symptoms. Infiltration of the tendon sheaths by granulocytes and macrophages as well as formation of osteoclasts next to the inflamed tendon sheaths were the first pathologic events. Tenosynovitis rapidly led to remodeling of the sheaths into pannus-like tissue, which formed osteoclasts that invaded the adjacent mineralized cartilage. Early lesions were associated with up-regulation of interleukin-1 (IL-1) and IL-6 as well as activation of p38 MAPK and ERK. In contrast, absence of osteoclasts led to uncoupling of tenosynovitis from invasion into cartilage and bone. TNF blockade also attenuated the pathologic changes associated with tenosynovitis.


CONCLUSIONS
Structural damage begins even before the onset of clinical symptoms of arthritis and involves the tendon sheaths as well as adjacent cartilage and bone. These results suggest that tenosynovitis is an initiating feature of arthritis and that joint destruction starts right from the onset of disease. Our findings thus underscore the importance of immediate initiation of an effective therapy in patients with rheumatoid arthritis.
Hayer
Silvia
S
Medical University of Vienna, Vienna, Austria.
Redlich
Kurt
K
Korb
Adelheid
A
Hermann
Sonja
S
Smolen
Josef
J
Schett
Georg
G
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001168:Arthritis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D002114:Calcinosis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis; D006801:Humans; D000069285:Infliximab; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007596:Joints / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000473:pathology*; D013717:Tenosynovitis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis
D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D007375:Interleukin-1; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases