Transthyretin deposition promotes progression of osteoarthritis

Abstract

SummaryDeposition of amyloid is a common aging‐associated phenomenon in several aging‐related diseases. Osteoarthritis (OA) is the most prevalent joint disease, and aging is its major risk factor. Transthyretin (TTR) is an amyloidogenic protein that is deposited in aging and OA‐affected human cartilage and promotes inflammatory and catabolic responses in cultured chondrocytes. Here, we investigated the role of TTR in vivo using transgenic mice overexpressing wild‐type human TTR (hTTR‐TG). Although TTR protein was detected in cartilage in hTTR‐TG mice, the TTR transgene was highly overexpressed in liver, but not in chondrocytes. OA was surgically induced by destabilizing the medial meniscus (DMM) in hTTR‐TG mice, wild‐type mice of the same strain (WT), and mice lacking endogenous Ttr genes. In the DMM model, both cartilage and synovitis histological scores were significantly increased in hTTR‐TG mice. Further, spontaneous degradation and OA‐like changes in cartilage and synovium developed in 18‐month‐old hTTR mice. Expression of cartilage catabolic (Adamts4, Mmp13) and inflammatory genes (Nos2, Il6) was significantly elevated in cartilage from 6‐month‐old hTTR‐TG mice compared with WT mice as was the level of phospho‐NF‐κB p65. Intra‐articular injection of aggregated TTR in WT mice increased synovitis and significantly increased expression of inflammatory genes in synovium. These findings are the first to show that TTR deposition increases disease severity in the murine DMM and aging model of OA.

Functional analysis of synovial fluid from osteoarthritic knee and carpometacarpal joints unravels different molecular profiles

“…To our knowledge, concentrations of IL10, IL6 and IFNG have not been reported in SF from OA CMC-I joints. Furthermore, IL6, IL10 and IFNG molecules are involved in similar molecular pathways as CCR6, TTR, CLU and PON1 [23,29,35,36]. In this work, an inverse relationship encompassing anti-inflammatory molecule, IL10 with CLU and PON1 was observed.…”

“…2). TTR has previously been implicated in OA pathogenesis, inflammatory responses and in inflammatory diseases such as RA and gout [23,24] [23]. CCR6 and its ligand CCL20 are known to be upregulated in OA cartilage.…”

Transthyretin amyloid deposits in lumbar spinal stenosis and assessment of signs of systemic amyloidosis

“…In the study on osteoarthritis by Rubin et al [44], no examination of the joint tissue was performed, but it was hypothesized that amyloid deposition could be directly pathogenic. This hypothesis was supported by a mouse model of osteoarthritis, where it was shown that the overexpression of TTR worsened the progression of the disease [45]. Taken together, the three studies indicate that ATTRwt amyloidosis is not only a cardiac disease.…”

The delaying effect of alpha-glycerophosphocholine on senescence, transthyretin deposition, and osteoarthritis in senescence-accelerated mouse prone 8 mice

“…As previously reported, TTR deposition in human OA cartilage was observed and exerted cytotoxicity for human chondrocytes [15]. Very recently, Matsuzaki et al have reported an intriguing mechanism by which TTR deposition promotes OA in murine models [32]. TTR deposition was found in the synovium of aged mice and enhanced inflammatory gene expression, resulting in OA progression.…”