Transthyretin deposition promotes progression of osteoarthritis

Tokio Matsuzaki, Yukio Akasaki, Merissa Olmer, Oscar Alvarez-Garcia, Natalia Reixach, Joel N. Buxbaum, Martin K. Lotz

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

Deposition 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.

Original languageEnglish
Pages (from-to)1313-1322
Number of pages10
JournalAging cell
Volume16
Issue number6
DOIs
Publication statusPublished - Dec 2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Ageing
  • Cell Biology

Fingerprint Dive into the research topics of 'Transthyretin deposition promotes progression of osteoarthritis'. Together they form a unique fingerprint.

Cite this