AIMP1 downregulation restores chondrogenic characteristics of dedifferentiated/degenerated chondrocytes by enhancing TGF-β signal

Abstract

Dedifferentiation and degeneration of chondrocytes critically influences the efficiency of cartilage repair. One of the causes is the defect of transforming growth factor (TGF)-β signaling that promotes chondrogenic differentiation and degeneration. In the present study, we found that aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1) negatively regulates TGF-β signaling via interactions with Smad2 and Smad3 in immunoprecipitation assay and luciferase assay. In addition, we observed that the AIMP1 expression level was significantly increased in osteoarthritis (OA) patient-derived degenerated chondrocytes compared with healthy control. So, we hypothesized that downregulation of AIMP1 using small-interfering RNA (siRNA) technology in dedifferentiated (collected at passage #6) and degenerated (obtained from OA-affected areas) chondrocytes could lead to recover TGF-β signaling in both chondrocytes. Indeed, AIMP1 downregulation restored TGF-β signaling by promoting phosphorylation of Smad2 and Smad3, which shows redifferentiated characteristics in both dedifferentiated and degenerated chondrocytes. Additionally, implantation analyses using in vivo mouse model clearly showed that AIMP1 downregulation resulted in the increased chondrogenic potential as well as the enhanced cartilage tissue formation in both dedifferentiated and degenerated chondrocytes. Histological analyses clarified that AIMP1 downregulation increased expression levels of collagen type II (Col II) and aggrecan, but not Col I expression. Taken together, these data indicate that AIMP1 downregulation using siRNA is a novel tool to restore TGF-β signaling and thereby increases the chondrogenic potential of dedifferentiated/degenerated chondrocytes, which could be further developed as a therapeutic siRNA to treat OA.

Genome-wide association study and predictive ability for growth traits in Nellore cattle

“…The genes AIMP1, TBCK, NPNT, INTS12, HAS2 and ICMT, could be related to muscle development, cellular and organs growth. The AIMP1 gene and TBCK, act potentially over the muscle tissues and cartilage development (AHN et al, 2016;ZHU et al, 2009), and in the actin organization, cell growth, and proliferation (LIU et al, 2013), respectively. The NPNT and INTS12 genes could be related to organs growth and regulation during gestation until birth (OBEIDAT et al, 2013;SUN et al, 2018).…”

Emerging potential of gene silencing approaches targeting anti-chondrogenic factors for cell-based cartilage repair

“…Nevertheless, increasing evidence strongly suggests that the silencing of key anti-chondrogenic regulators may be effectively employed to enhance or even induce chondrogenesis, stimulate the production of cartilage matrix, and improve or stabilize the chondrocytic phenotype [21][22][23][24].…”

“…Enhanced cartilage tissue formation in vivo [23] ANGPTL4 Lipid metabolism Increased expression of collagen II and aggrecan, and suppression of MMP1, 3 and 13 in hMSCs [37] A. Lolli et al and help to preserve the integrity of articular cartilage.…”

“…Interesting findings concern aminoacyl tRNA synthetase complex interacting multifunctional protein 1 (AIMP1), angiopoietin-like 4 (ANGPTL4), and VEGF. AIMP1 negatively regulates the TGF-b signaling by preventing SMAD2/3 phosphorilation, and a siRNA against AIMP1 was effective in rescuing the chondrogenic potential of dedifferentiated and OA human chondrocytes, in vitro and in vivo [23]. Treatment of hMSCs with a specific siRNA against ANGPTL4 prior to chondrogenesis increased the expression of collagen type II and aggrecan, while repressing the expression of MMPs [37].…”

Roles of aminoacyl-tRNA synthetase-interacting multi-functional proteins in physiology and cancer

“…Interestingly, accumulating evidence has identified that AIMPs participate in various physiological and pathological processes as multifaceted molecules 10 – 13 . It was reported that the downregulation of AIMP1 enhanced transforming growth factor-β (TGF-β) signal by inducing the phosphorylation of Smad family member 2/3 (Smad2/3), which in turn promoted the chondrogenic potential of dedifferentiated/degenerated chondrocytes 14 . Furthermore, patients with a homozygous c.105C>A (p.Tyr35Ter) mutation in AIMP2 showed microcephaly, seizures, mental retardation, and spastic quadriplegia 15 .…”