Background/Purpose

Deposition of amyloid is a common aging-associated phenomenon and a key factor in the pathogenesis of several aging-related diseases. Osteoarthritis is the most prevalent joint disease and aging is its major risk factor. Although amyloid deposits appear to be a prevalent in OA-affected joints, their composition and effects on cell and tissue function are unknown. Transthyretin (TTR) is an amyloidogenic protein. Point mutations in the TTR gene cause of familial amyloidotic polyneuropathy and cardiomyopathy. Wild-type TTR can also assemble into amyloid deposits and this may be facilitated by oxidation, or the presence of sulfated glycosaminoglycans. This study addressed TTR deposition in aging and OA-affected knee cartilage and effects of TTR on chondrocyte function.

Methods

Amyloid deposition in normal and OA human knee cartilage was determined by Congo-red staining and polarized light microscopy. TTR in cartilage and synovial fluid was analyzed by immunohistochemistry and western blotting. TTR gene expression in chondrocytes was studied by quantitative PCR and RNA sequencing. Effects of wild type and mutant TTR were studied in normal human chondrocyte cultures with measurements of cell viability and OA-related gene expression.

Results

There was no amyloid deposition in young normal cartilage. In contrast, 58% (7/12) of aged normal cartilage and 100% (12/12) of OA cartilage samples had Congo red staining. TTR was detectable in all OA and a majority of aged but not in young normal cartilage and predominantly located at the cartilage surfaces. TTR is not produced by chondrocytes at substantial levels and synovial fluid levels are similar in normal and OA affected knees. In chondrocytes, TTR induces cell death, the expression of proinflammatory cytokines and extracellular matrix degrading enzymes. This was observed for the amyloidogenic but not for the non-amyloidogenic TTR mutant. Effects of TTR on cell viability and gene expression are mediated by activation of TLR4 signaling and MAP kinases.

Conclusion

These findings are the first to suggest that TTR amyloid deposition may not represent an inconsequential aging-related phenomenon but contribute to cell and extracellular matrix damage in articular cartilage.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/transthyretin-and-amyloid-in-cartilage-aging-and-osteoarthritis/