Genetic deficiency of nuclear factor of activated T cells 5 attenuates the development of osteoarthritis in mice

• Published in: Joint, bone, spine : revue du rhumatisme bone, spine : revue du rhumatisme, 2022-01, Vol.89 (1), p.105273-105273, Article 105273
• Main Authors: Lee, Jinhee, Lee, Jongmin, Lee, Saseong, Yoo, Seung-Ah, Kim, Ki-Myo, Kim, Wan-Uk, Cho, Chul-Soo, Yoon, Chong-Hyeon
• Format: Article
• Language: English
• Subjects: Animals; Cartilage, Articular - pathology; CCL2; Cells, Cultured; Chondrocytes; Factor V - metabolism; Factor V - pharmacology; Factor V - therapeutic use; Humans; Interleukin-1beta - metabolism; Interleukin-1beta - pharmacology; Interleukin-1beta - therapeutic use; Male; Mammals - metabolism; Mice; Mice, Inbred C57BL; NFAT5; Osteoarthritis; Osteoarthritis - metabolism; Synovial inflammation; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; Transcription Factors - metabolism
• ISSN: 1297-319X; 1778-7254
• DOI: 10.1016/j.jbspin.2021.105273

•NFAT5 is highly expressed in the knee joint of mouse osteoarthritis (OA) model.•NFAT5 is a crucial regulator of OA pathogenesis by upregulating CCL2 expression and macrophage recruitment.•Genetic disruption of NFAT5 attenuates synovial inflammation and cartilage damage in OA.•NFAT5 could be an attractive therapeutic target for OA treatment. This study is aimed to investigate the role of nuclear factor of activated T cells 5 (NFAT5), originally known as the osmosensitive mammalian transcription factor, in the pathogenesis of osteoarthritis (OA) in mice. OA was induced in male C57BL/6 (wild-type) and NFAT5 haplo-insufficient (NFAT5+/–) mice via destabilization of the medial meniscus (DMM) surgery. OA severity and synovial inflammation were histologically assessed. Expression of CCL2, inflammatory cytokines, cartilage degrading enzymes was determined in the knee joints and cultured chondrocytes from wild-type and NFAT5+/− mice. NFAT5 expression was significantly upregulated in the knee joint of a mouse after DMM surgery. NFAT5 deficiency decreased the severity of synovial inflammation and osteoarthritic changes in cartilage and subchondral bone. Moreover, NFAT5 deficiency also decreased the expression of CCL2, IL-1β, MMP-13, ADMATS-5, and macrophage infiltration in the joint. In cultured chondrocytes, hyperosmolar or IL-1β stimulation significantly enhanced the expression of NFAT5, CCL2, IL-1β, IL-6, and MMP-13, and this effect was abolished in chondrocytes from NFAT5+/− mice. Hyperosmolarity or IL-1β-induced NFAT5 and CCL2 downregulated by inhibiting p38 MAPK, JNK, and ERK pathways. Our results indicate that NFAT5 is a crucial regulator of OA pathogenesis by upregulating CCL2 expression and macrophage recruitment. In chondrocyte, NFAT5 plays an important role in the response to hyperosmolar or IL-1β stimulation. Thus, NFAT5 could be an attractive therapeutic target for OA treatment.