Date: Sunday, November 5, 2017
Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: The mechanism of chondrocyte mechanotransduction is not fully understood. Recently, transient receptor potential vanilloid 4 (TRPV4) has been reported to transduce dynamic compressive loading in articular chondrocytes. The expression of the IL-1 receptor 1 (IL-1R1) on the surface of chondrocytes can be stimulated by compressive stress, and such increment of IL-1 susceptibility has been implicated in the OA pathology. The purpose of this study was to examine mechanical induction of IL-1R1 by chondrocytes in three-dimensional (3D) culture, and the effects of TRPV4 channel regulation on IL-1R1 expression. Methods: Mouse embryonal carcinoma-derived clonal cell line (ATDC5) was used and cultured in alginate beads with the growth medium for 6 days. These cells were collected and seeded in collagen gels and scaffolds, which maintained chondrogenic phenotype in 3D environment (Fig.1). Cyclic compressive loading of 40 kPa at 0.5Hz was applied to this 3D constructs using a cyclic load bioreactor for 3 hours. Thereafter, the PGE2 concentration and mRNA expressions of Col-II, ADAMTS4 and IL-1R1 were measured in real-time PCR. The effects of subtle amount of IL-1beta (1pg/ml) was determined with or without compressive stress, and the effects of TRPV4 agonist/antagonist on IL-1-induced ADAMTS4 was determined. Results: The PGE2 production in culture media and mRNA levels of ADAMTS4 and IL-1R1 were substantially increased by the excessive compressive stress. Compressive stress plus IL-1beta (1pg/ml) upregulated ADAMTS4 and IL-1R1 expressions by 3-fold and 8-fold, respectively, but IL-1beta alone failed to do so (Fig.2). TRPV4 agonist suppressed upregulation of ADAMTS4 and IL-1R1 mRNAs by cyclic compressive stress, conversely, TRPV4 antagonist rather accelerated these mRNA expressions (Fig.3). Conclusion: In chondrogenic 3D environment, the cells gained IL-1 susceptibility under excessive cyclic compressive stress. In this context, the cells would produce ADAMTS4 and MMPs in response to subtle level of IL-1 derived from synovia or cartilage itself, whereas TRPV4 downregulated expression of IL-1R1 and control IL-1 susceptibility to maintain cartilage homeostasis. To control IL-1 susceptibility is a key to prevent the development of OA, when excessive mechanical stress is applied on the articular cartilage.
To cite this abstract in AMA style:Takeda Y, Niki Y, Fukuhara Y, Fukuda Y, Udagawa K, Kikuchi T, Miyamoto T, Matsumoto M, Nakamura M. Excessive Cyclic Compressive Stress Increases Susceptibility to IL-1 in 3D-Cultured Chondrocytes [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/excessive-cyclic-compressive-stress-increases-susceptibility-to-il-1-in-3d-cultured-chondrocytes/. Accessed August 14, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/excessive-cyclic-compressive-stress-increases-susceptibility-to-il-1-in-3d-cultured-chondrocytes/