PR11‐364P22.2/ATF3 protein interaction mediates IL‐1β‐induced catabolic effects in cartilage tissue and chondrocytes

Abstract

Osteoarthritis (OA) is a degenerative joint disease which lacks effective medical treatment due to ill‐defined molecular mechanisms underlying the pathology. Inflammation is a key factor that induces and aggravates OA. Therefore, the current study aims to explore roles of the dysregulated long non‐coding RNAs in the pro‐inflammatory cytokine IL‐1β‐mediated catabolic effects in cartilage tissue and chondrocytes. We identified RP11‐364P22.2 as dysregulated in OA patient‐derived cartilage tissues and highly responsive to IL‐1β stimulus. RNA pull‐down coupled with mass spectrometry demonstrated that RP11‐364P22.2 physically binds to activating transcription factor 3 (ATF3) and thus increases the protein stability and facilitates its nuclear translocation. Loss‐ and gain‐of‐function assays indicated that the interaction between RP11‐364P22.2 and ATF3 is indispensable for the detrimental effects of IL‐1β including growth inhibition, apoptosis induction as well as degradation of the key chondrocyte structural proteins of type II collage and Aggrecan and synthesis of the extracellular matrix‐degrading enzyme MMP13 in chondrocytes. In vivo, depletion of the RP11‐364P22.2 effector ATF3 drastically prevented OA development in the rats with surgical destabilization of the medial meniscus (DMM). These results highlight the important roles of lncRNAs in the pathogenesis of OA and indicate the RP11‐364P22.2/ATF3 regulatory axis as a potential therapeutic target of inflammation‐induced OA.

Silencing ATF3 Might Delay TBHP-Induced Intervertebral Disc Degeneration by Repressing NPC Ferroptosis, Apoptosis, and ECM Degradation

“…ATF3 belongs to the ATF/cyclic AMP-responsive element binding (CREB) protein family that exerts its transcriptional inhibition or activation effect through interaction with other ATF/CREB members or TFs or binding to its target genes' promoters [ 16 ]. The abnormal expression and dysfunction of ATF3 could contribute to a series of pathophysiological responses, including cell death, inflammatory response, ECM metabolism disorder, oxidative stress, endoplasmic reticulum stress [ 16 , 42 ], and even diseases, such as osteoarthritis [ 43 – 45 ], cancer [ 16 ], and cardiovascular diseases [ 42 ]. In chondrocytes, ATF3 was expressed in the nucleus and cytoplasm [ 43 – 45 ].…”

“…The abnormal expression and dysfunction of ATF3 could contribute to a series of pathophysiological responses, including cell death, inflammatory response, ECM metabolism disorder, oxidative stress, endoplasmic reticulum stress [ 16 , 42 ], and even diseases, such as osteoarthritis [ 43 – 45 ], cancer [ 16 ], and cardiovascular diseases [ 42 ]. In chondrocytes, ATF3 was expressed in the nucleus and cytoplasm [ 43 – 45 ]. Iezaki et al [ 43 ] found that the expression of ATF3 was significantly upregulated in the osteoarthritis cartilage of both mice and humans, and the knockdown of ATF3 in chondrocytes decreased cytokine-induced IL-6 transcription by inhibiting NF- κ B signaling to alleviate the development of osteoarthritis.…”

“…The relationship between ncRNA and ATF3 has also been studied in chondrocytes. ncRNA RP11-364P22.2 could bind to ATF3 and facilitate its nuclear translocation, thereby promoting chondrocyte apoptosis and ECM degradation [ 45 ]. NPCs have similar biological characteristics and functions as chondrocytes.…”

CRISPR signal conductor 2.0 for redirecting cellular information flow

“…To determine whether CRISPR-dCasΦ system can upregulate the expression of the genes of interest by fusing the crRNA with lncRNA functional motifs that can bind to transcription activators, we separately inserted the lncRNA motifs that bind to the transcription activators ATF3 41 , MYC 42 , STAT3 43 , and YBX1 44 into the 5′-end of crRNAs to construct a series of transcription activation devices (Fig. 2a ).…”

Inhibition of HMGB1 suppresses inflammation and catabolism in temporomandibular joint osteoarthritis <em>via</em> NF-κB signaling pathway

“…6 Inflammation is a common accompaniment and contributes to the development of OA, characterized by a large number of pro-inflammatory mediators including cytokines including IL-1β and IL-6 and chemokines of innate immune response to joint injuries. 7,8) Pro-inflammatory cytokines such as IL-1β promote progressive degeneration of the articular cartilage through the production of matrix metalloproteinase (MMPs), 9 which degrade extracellular matrix components, including collagen and proteoglycans. 10 IL-1β may also induce other proinflammatory cytokines such as IL-6 and IL-8 expression in chondrocytes and synovial fibroblasts.…”