Transthyretin Deposition Accelerates the Development of Experimental Osteoarthritis in Mice

Tokio Matsuzaki¹, Oscar Alvarez-Garcia², Yukio Akasaki³, Natalia Reixach⁴, Joel Buxbaum² and Martin K. Lotz⁵, ¹Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, ²The Scripps Research Institute, La Jolla, CA, ³Kyushu University, Fukuoka, Japan, ⁴Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, ⁵Division of Arthritis, The Scripps Research Institute, La Jolla, CA

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: cartilage and osteoarthritis

Session Information

Date: Monday, November 9, 2015

Title: Biology and Pathology of Bone and Joint Poster I: Osteoarthritis Pathogenesis

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose:

Deposition of amyloid is a common aging-associated phenomenon and a key factor in the pathogenesis of 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. We previously reported that amyloid and TTR deposition were increased in human OA cartilage with aging and OA grade. In addition, amyloidogenic TTR affected chondrocyte survival and induced the OA related genes such as ADAMTS4, interleukin 6 and inducible nitric oxide synthase. Here we investigated the role of TTR in vivo. Transgenic mice for wild-type human TTR (hTTR TG mice) were analyzed using an experimental OA model.

Methods:

TTR in cartilage and chondrocytes was analyzed by immunohistochemistry and Western blotting. OA was surgically induced by destabilizing the medial meniscus of the hTTR TG mice (n=26) and control mice (n=22). Mice were sacrificed 10 weeks after surgery. To investigate the effects of TTR on cartilage, 6-month-old mice were sacrificed and examined by immunohistochemistry, real-time PCR and Western blotting. In addition, quantitative analysis of cell number in cartilage was examined in 6-, 12-month-old mice, and surgical model. OA-related tissue changes were evaluated using the Glasson’s semi-quantitative cartilage scoring system and Krenn’s synovitis score.

Results:

TTR protein was detected in cartilage in hTTR TG mice, but chondrocytes did not express TTR mRNA, the transgene was highly overexpressed in the liver. ADAMTS4 and MMP13 mRNA were significantly elevated in cartilage in 6 month-old hTTR TG mice compared with control mice. Immunohistochemical and Western blotting analysis showed increased MMP13 expression in the hTTR TG mice 10 weeks after surgery compared with control mice. In addition, nuclear factor-κB (NF-κB) p65 and Phospho-NF-κB p65 was elevated in hTTR TG mice. In the surgical model, both histological OA score and synovitis score were significantly increased in hTTR TG mice. Additionally, cellularity was significantly lower in the 6-month-old hTTR TG mice and hTTR TG mice with surgical OA compared with control mice.

Conclusion:

These findings are the first to show that TTR deposition accelerated the development of OA in the surgically-induced murine OA model. Our observations suggested that reducing TTR amyloid formation can be a new therapeutic approach for OA.

Disclosure: T. Matsuzaki, None; O. Alvarez-Garcia, None; Y. Akasaki, None; N. Reixach, None; J. Buxbaum, None; M. K. Lotz, None.

To cite this abstract in AMA style:

Matsuzaki T, Alvarez-Garcia O, Akasaki Y, Reixach N, Buxbaum J, Lotz MK. Transthyretin Deposition Accelerates the Development of Experimental Osteoarthritis in Mice [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/transthyretin-deposition-accelerates-the-development-of-experimental-osteoarthritis-in-mice/. Accessed .

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