Transthyretin deposition in articular cartilage: a novel mechanism in the pathogenesis of osteoarthritis.
OBJECTIVE
Amyloid deposits are prevalent in osteoarthritic (OA) joints. We undertook this study to define the dominant precursor and to determine whether the deposits affect chondrocyte functions.


METHODS
Amyloid deposition in human normal and OA knee cartilage was determined by Congo red staining. Transthyretin (TTR) in cartilage and synovial fluid was analyzed by immunohistochemistry and Western blotting. The effects of recombinant amyloidogenic and nonamyloidogenic TTR variants were tested in human chondrocyte cultures.


RESULTS
Normal cartilage from young donors did not contain detectable amyloid deposits, but 7 of 12 aged normal cartilage samples (58%) and 12 of 12 OA cartilage samples (100%) had Congo red staining with green birefringence under polarized light. TTR, which is located predominantly at the cartilage surfaces, was detected in all OA cartilage samples and in a majority of aged normal cartilage samples, but not in normal cartilage samples from young donors. Chondrocytes and synoviocytes did not contain significant amounts of TTR messenger RNA. Synovial fluid TTR levels were similar in normal and OA knees. In cultured chondrocytes, only an amyloidogenic TTR variant induced cell death as well as the expression of proinflammatory cytokines and extracellular matrix-degrading enzymes. The effects of amyloidogenic TTR on gene expression were mediated in part by Toll-like receptor 4, receptor for advanced glycation end products, and p38 MAPK. TTR-induced cytotoxicity was inhibited by resveratrol, a plant polyphenol that stabilizes the native tetrameric structure of TTR.


CONCLUSIONS
These findings are the first to suggest that TTR amyloid deposition contributes to cell and extracellular matrix damage in articular cartilage in human OA and that therapies designed to reduce TTR amyloid formation might be useful.
The Scripps Research Institute, La Jolla, California.
Yukio
Y
Akasaki
The Scripps Research Institute, La Jolla, California.
Natàlia
N
Reixach
The Scripps Research Institute, La Jolla, California.
Tokio
T
Matsuzaki
The Scripps Research Institute, La Jolla, California.
Oscar
O
Alvarez-Garcia
The Scripps Research Institute, La Jolla, California.
Merissa
M
Olmer
Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Yukihide
Y
Iwamoto
The Scripps Research Institute, La Jolla, California.
Joel N
JN
Buxbaum
The Scripps Research Institute, La Jolla, California.
Martin K
MK
Lotz
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058227:Amyloidogenic Proteins / Q000378:metabolism* / Q000494:pharmacology; D015153:Blotting, Western; D002358:Cartilage, Articular / Q000378:metabolism*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000378:metabolism*; D011228:Prealbumin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013582:Synovial Fluid / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000187:drug effects / Q000378:metabolism; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism
D058227:Amyloidogenic Proteins; D011228:Prealbumin; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D048051:p38 Mitogen-Activated Protein Kinases