Earlier this year researchers published evidence suggesting that rising levels of transthyretin (TTR) amyloid may contribute to age-related damage to cartilage tissue in joints and consequent development of osteoarthritis. Amyloids of various types accumulate in tissue with advancing age, each resulting from a different misfolded protein whose altered properties in that state cause it to form solid deposits. The biochemistry of this process is different in each case, and usually complex and incompletely understood. You don't have to look any further than the field of Alzheimer's research and the still dominant amyloid hypothesis to see that investigations of amyloid biochemistry are enough to keep most of a sizable scientific industry busy for decades. Knowledge of amyloid-β has grown in proportion to the funding and attention directed to the Alzheimer's research community, but for many of the other forms of amyloid it isn't entirely clear as to exactly how their presence contributes to the age-related conditions that correlate with the presence.
In some cases this is because the data is still arriving: researchers were not looking in the right place, or not paying enough attention, or lacked funding for the necessary investigations. TTR amyloidosis is an excellent example of this situation, as until fairly recently the majority of research interest focused on the rare inherited form of the condition, which is caused by genetic mutation and leads to an abnormally rapid accumulation of amyloid. Then it was discovered that a sizable fraction of supercentenarians die due to TTR amyloidosis, the condition called senile systemic amyloidosis in this case to distinguish it from the inherited form. In essence this form of amyloid builds up in the cardiovascular system of the most elderly people, attaining a large enough presence to choke proper function of the heart. Later, in the past couple of years, researchers have found signs of the damage done by TTR amyloid in a range of age-related conditions: as a contributing cause of spinal stenosis; as an unsuspected contribution to heart failure in a much wider group of old people; and now in the progressive destruction of cartilage.
The silver lining here is that promising therapies capable of breaking down TTR amyloid are under development. The more that we see this amyloid involved in age-related degeneration, the happier we should be given ongoing progress towards a basis for effective treatments. The SENS Research Foundation has funded work on catabodies that can degrade TTR amyloid, other groups have made inroads into disrupting amyloid formation, while earlier this year a human trial of small molecule drugs to clear TTR amyloid reported good results.
Amyloid deposits are prevalent in osteoarthritic joints. We undertook this study to define the dominant precursor and to determine whether the deposits affect chondrocyte functions. Amyloid deposition in human normal and osteoarthritic 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.
Normal cartilage from young donors did not contain detectable amyloid deposits, but 7 of 12 aged normal cartilage samples (58%) and 12 of 12 osteoarthritic 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 osteoarthritic 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 osteoarthritic 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.
These findings are the first to suggest that TTR amyloid deposition contributes to cell and extracellular matrix damage in articular cartilage in human osteoarthritis and that therapies designed to reduce TTR amyloid formation might be useful.