Additional Evidence for Transthyretin Amyloid to Contribute to Osteoarthritis

The accumulation of transthyretin amyloid deposits in tissues is one of the contributing causes of aging. There are perhaps a score of different amyloids found in older humans, each the solid form of a particular protein broken in a particular way, and all a side-effect of the normal operation of cellular metabolism. In some cases it isn't all that clear as to what harms an amyloid causes, while at the other end of the spectrum of knowledge lies the amyloid-β associated with Alzheimer's disease - a very active and well-funded research community has mapped a great deal of the biochemistry of this amyloid and the ways in which it produces dysfunction and death in brain cells. I suspect that were the same level of attention directed towards other amyloids, harms would be identified. As supporting evidence for this hypothesis, I'll note that over the years transthyretin amyloid has been moving steadily from scientific ignorance of the damage it does towards a greater understanding of the negative impacts it has on health and mortality.

Nearly a decade ago, investigations into the causes of mortality in supercentenarians pointed to transthyretin amyloid as a majority cause of death: it chokes the cardiovascular system, leading to heart failure. It may well be that transthyretin amyloidosis provides the present outer limit to human life span, or at least until it is addressed. A couple of years ago, researchers associated transthyretin amyloid with heart failure in younger cohorts of old people - it isn't just the oldest old who are impacted significantly by amyloid in heart tissue. Another line of research that has developed in the past few years is the association of transthyretin amyloid with cartilage degeneration and osteoarthritis, which is the topic of the open access paper noted below, as well as in related conditions such as spinal stenosis.

A number of different approaches to clearing out transthyretin amyloid are in development. They are a little further along, on average, than much of the portfolio of potential rejuvenation therapies largely because of the existence of a rare inherited condition, transthyretin-related hereditary amyloidosis, in which mutation leads to the rampant accumulation of this amyloid at a young age. However, funding should expand and progress speed up the more that transthyretin amyloid is conclusively linked to common age-related conditions. Among the efforts worth keeping an eye on: a few years ago, a trial successfully demonstrated clearance of amyloid using a combination of CPHPC and anti-SAP antibodies; the SENS Research Foundation has funded work on catalytic antibodies for amyloid; there are other antibody initiatives at varying stages; and RNA interference also seems promising. One or more of these approaches will push forward into clinical availability sooner or later. When successful this will join the ranks of other proven rejuvenation therapies: ways to turn back the causes of multiple age-related diseases by repairing the forms of cell and tissue damage that lie at the root of aging.

Transthyretin deposition promotes progression of osteoarthritis

Osteoarthritis (OA) is the most prevalent human joint disease with age being the main risk factor. There are currently no established approaches to prevent or slow the progression of OA. A large number of therapeutic targets have been identified and successfully tested in animal models. However, thus far clinical trials targeting these pathways have failed. Changes in articular cartilage appear to be the earliest event in disease initiation and are likely to be the main drivers of disease progression, but all the joint tissues are affected by the disease process. Age-related changes in cartilage have been characterized, but the mechanisms that mediate the effect of age on OA are unknown.

In studies of articular cartilage, menisci, and synovium from arthritic joints, the prevalence of amyloid deposits was between thirty and one hundred percent of joints examined. Amyloid deposits in OA synovium were ranged from 8% to 25% of the patients. The most common precursor is the thyroxin (T4) and retinol transporter protein transthyretin (TTR). TTR is protein is composed of four identical subunits. TTR amyloid formation requires tetramer dissociation into monomers that misfold and aggregate to initiate the amyloidosis cascade. In contrast with the less common forms of inherited transthyretin amyloidosis, the more prevalent senile systemic amyloidosis (SSA) is caused by the deposition of amyloid derived from wild-type TTR. It occurs mainly in elderly males, with its clinically dominant manifestations related to deposits of wild-type TTR in the myocardium.

We have previously reported that all human cartilage samples collected at the time of joint replacement surgery were positive for amyloid and TTR. In addition, we showed in studies of primary cultured chondrocytes that exposure to amyloidogenic TTR affected chondrocyte survival and induced the expression of OA-related genes. These findings raise the question of whether the deposits contribute to the process of cartilage degradation. It is also possible that the damaged tissues create an environment which supports TTR aggregation, which in turn could amplify the OA process. The objective of this study was to investigate the role of TTR in vivo in mice transgenic for 90-100 copies of the wild-type human TTR (hTTR-TG mice) using an experimental OA and aging model.

We used mice with transgenic overexpression of human rather than mouse TTR as the mouse protein is kinetically several orders of magnitude more stable than the human protein and hence is not subject to amyloid formation, which depends on tetramer dissociation. The hTTR-TG mouse strain that we have studied showed human TTR deposits between 12 and 17 months of age in the kidneys and heart. In mice over 18 months of age, TTR-related deposits were found in 84% in the kidneys and 39% in the heart. The main observation from the present study is that hTTR-TG mice develop more severe cartilage damage and synovitis than wild-type mice in the surgically induced OA model and aging model. This suggests that OA-related cartilage changes promote TTR deposition, which, in turn, seems to amplify the OA damage.

The hTTR-TG mice did not present abnormalities in skeletal development and there were no differences in joint pathology compared to wild-type mice by 12 months. However, at 18 months, hTTR-TG mice developed significantly increased OA degeneration and synovial changes compared to wild-type. One of the main mechanisms of TTR amyloid pathogenesis is cytotoxicity. We showed that amyloidogenic TTR-induced cell death in cultured chondrocytes and one of the histological features of the hTTR mice was reduced cartilage cellularity. Thus, it appears that this is also one factor contributing to the increased OA severity in these mice. Together with prior observations that aging and OA in humans are associated with TTR and amyloid deposition in cartilage, the present findings suggest that reducing TTR amyloid formation can be a new therapeutic approach for OA.

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