Mammalian target of rapamycin signaling is crucial for joint destruction in experimental arthritis and is activated in osteoclasts from patients with rheumatoid arthritis.
OBJECTIVE
Activation of the mammalian target of rapamycin (mTOR) pathway is important for immune cell activation and bone metabolism. To date, the contribution of mTOR signaling to joint inflammation and structural bone and cartilage damage is unknown. The aim of this study was to investigate the potential of inhibiting mTOR as a treatment of inflammatory arthritis.


METHODS
Human tumor necrosis factor-transgenic mice in which inflammatory arthritis was developing were treated with 2 different mTOR inhibitors, sirolimus or everolimus. The effects of treatment on clinical disease activity, inflammation, and localized joint and cartilage destruction were studied. In addition, the effects of mTOR inhibition on osteoclast survival and expression of key molecules of osteoclast function were analyzed in vitro. Moreover, synovial tissue from patients with rheumatoid arthritis (RA) was assessed for activation of the mTOR pathway.


RESULTS
Inhibition of mTOR by sirolimus or everolimus reduced synovial osteoclast formation and protected against local bone erosions and cartilage loss. Clinical signs of arthritis improved after mTOR inhibition, and histologic evaluation showed a decrease in synovitis. In vitro, mTOR inhibition down-regulated the expression of digestive enzymes and led to osteoclast apoptosis. Moreover, mTOR signaling was shown to be active in the synovial membrane of patients with RA, particularly in synovial osteoclasts.


CONCLUSIONS
Signaling through mTOR is an important link between synovitis and structural damage in inflammatory arthritis. Current pharmacologic inhibitors of mTOR could be effective in protecting joints against structural damage.
Cejka
Daniel
D
Medical University of Vienna, Vienna, Austria.
Hayer
Silvia
S
Niederreiter
Birgit
B
Sieghart
Wolfgang
W
Fuereder
Thorsten
T
Zwerina
Jochen
J
Schett
Georg
G
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D002478:Cells, Cultured; D000068338:Everolimus; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007596:Joints / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases; D048069:Tumor Necrosis Factors / Q000378:metabolism
D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D048069:Tumor Necrosis Factors; D000068338:Everolimus; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus