FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration

Abstract

Intervertebral disk (IVD) degeneration is a prevalent age‐associated musculoskeletal disorder and a major cause of chronic low back pain. Aging is the main risk factor for the disease, but the molecular mechanisms regulating IVD homeostasis during aging are unknown. The aim of this study was to investigate the function of FOXO, a family of transcription factors linked to aging and longevity, in IVD aging and age‐related degeneration. Conditional deletion of all FOXO isoforms (FOXO1, 3, and 4) in IVD using the Col2a1Cre and AcanCreER mouse resulted in spontaneous development of IVD degeneration that was driven by severe cell loss in the nucleus pulposus (NP) and cartilaginous endplates (EP). Conditional deletion of individual FOXO in mature mice showed that FOXO1 and FOXO3 are the dominant isoforms and have redundant functions in promoting IVD homeostasis. Gene expression analyses indicated impaired autophagy and reduced antioxidant defenses in the NP of FOXO‐deficient IVD. In primary human NP cells, FOXO directly regulated autophagy and adaptation to hypoxia and promoted resistance to oxidative and inflammatory stress. Our findings demonstrate that FOXO are critical regulators of IVD homeostasis during aging and suggest that maintaining or restoring FOXO expression can be a therapeutic strategy to promote healthy IVD aging and delay the onset of IVD degeneration.

MicroRNA-221 silencing attenuates the degenerated phenotype of intervertebral disc cells

“…In our effort to elucidate the molecular mechanisms supporting miR-221 action in IVD cells, we focused on the effect of antagomiR-221 treatment on FOXO3, a member of forkhead ‘O’ class transcription factors that have been recently defined as critical mediators of IVD integrity and function [ 16 , 17 ]. Computational analysis performed with three miRNA databases (miRanda, DIANA-microT v5.0 and miRTarBase) on the 3′ UTR sequence of FOXO3 identified possible binding sites for miR-221.…”

“…Notably, antagomiR-221 treated cells restored higher levels of FOXO3 and TRPS1 attenuating the grade of severity based on a molecular point of view. The appearance of FOXO3 (a miR-221 validated target in other contexts) after antagomiR-221 treatment together with the demonstration that miR-221 directly targets FOXO3 also in IVD cells is an important evidence, since the expression of this crucial transcription factor significantly decreased in human degenerated discs [ 16 , 17 ].…”

Regulation of terminal hypertrophic chondrocyte differentiation in Prmt5 mutant mice modeling infantile idiopathic scoliosis

“…Meanwhile, the translation of mechanical loading signals activates TGFβ signaling, which promotes IVD homeostatic processes (Bian et al, 2017). Recent studies also show that Runx2 is required for postnatal IVD maintenance (Alvarez-Garcia et al, 2018;Liao et al, 2019). Here, we found that postnatal loss of PRMT5 in cartilaginous lineages of the spine resulted in alterations in the normal gene expression in IVD and vertebral growth plate, including reduced expression of Prg4 as well as increased expression of COLX, which are both markers of early-onset degenerative disc.…”

“…During postnatal development, chondrocytes continue to regulate spine homeostasis by maintaining a dynamic balance between the synthesis and degradation of extracellular matrix components in the cartilaginous tissues of the spine. These processes are regulated in part by key transcriptional regulators, including SOX9 (Henry et al, 2012) and RUNX2 (Alvarez-Garcia et al, 2018;Liao et al, 2019).…”

Electroacupuncture Alleviates Experimental Chronic Inflammatory Pain by Inhibiting Calcium Voltage‐Gated Channel‐Mediated Inflammation

“…Moreover, the FoxO signaling pathway (rno04068, p value � 4.735e − 02) and MAPK signaling pathway (rno04010, p value � 4.672e − 02) were also significantly enriched. Many studies have reported that the FoxO and MAPK signaling pathway can regulate apoptotic activity involved in pain or the nervous system [31][32][33]. erefore, we speculate that EA can reverse the aberrant apoptotic activity in DRG neurons in CIP rats through the MAPK or/and signaling pathway.…”