Intervertebral disc degeneration (IDD) is considered as a dominant contributor to low back pain (LBP), causing severe pain, limited range of lumbar motion, physical dysfunction, and restriction of social activity. However, the specific pathological mechanisms underlying IDD remain elusive, and effective strategies to delay the pathogenesis of IDD are still unclear and limited. In recent years, some studies have found that nuclear factor erythroid 2-related factor 2 (Nrf2), an important antioxidant transcription factor, may play crucial roles in the pathogenesis and progression of age-related diseases including IDD. Nrf2 can maintain redox homeostasis and protecting nucleus pulposus (NP) cells against oxidative stress, inflammatory response, extracellular matrix (ECM) catabolism, cell senescence and cell death involving in the progression of IDD. In this review, we aim to systematically describe the vital roles and pathological mechanism of Nrf2 signaling axis in the pathogenesis of IDD, which may put forward potential therapeutic strategies for the prevention and treatment of IDD by targeting Nrf2.

Objective: The aim of this work is to investigate the impact of exercise on gut microbiome composition, serum metabolites, and their correlation with osteoarthritis (OA) severity. Methods: Thirty-six Sprague-Dawley (SD) rats were randomly divided into four groups: Sham rats without treadmill walking (Sham/Sed group, n = 9), Sham rats with treadmill walking 2 months (Sham/TW2M group, n = 9), PTOA rats without treadmill walking (PTOA/Sed group, n = 9), and PTOA rats with treadmill walking 2 months (PTOA/TW2M group, n = 9). The PTOA model was induced by transection of the anterior cruciate ligament (ACLT) and destabilization of the medial meniscus (DMM). Histological evaluation and micro-CT analysis were performed to observe the pathological changes in cartilage and subchondral bone, respectively. Additionally, we conducted 16S rDNA sequencing of fecal samples and untargeted metabolomic analysis using liquid chromatography–mass spectrometry (LC–MS) of serum samples to detect the alteration of gut microbiota composition and metabolites. Results: Exercise effectively mitigated OA-related pathological changes, including articular cartilage degeneration and subchondral bone loss. Moreover, 16S rDNA sequencing analysis of gut microbiome revealed a decreased abundance of Bacteroidetes (p < 0.01), Bacteroidia (p < 0.01), Rikenellaceae (p < 0.01), [Paraprevotellaceae] (p < 0.01), and Paraprevotella (p < 0.01) but an increase in Firmicutes (p < 0.01) in PTOA/TW2M group rats compared with PTOA/Sed group as a response to exercise. In addition, the results of metabolomics analysis showed that exercise treatment contributed to the upregulation of Daidzein and Anthranilic acid and downregulation of 1-Palmitoyllysophosphatidylcholine. Moreover, the correlation analysis showed that Rikenellaceae significantly positively correlated with both OARSI (r = 0.81, p < 0.01) and Mankin score (r = 0.83, p < 0.01) and negatively correlated with the serum level of Anthranilic acid (r = −0.56, p < 0.01) and Daidzein (r = −0.46, p < 0.01). Conclusions: Exercise can effectively mitigate OA through slowing down articular cartilage degeneration and subchondral bone loss, modulating gut microbiota composition, and increasing beneficial metabolites.

This study aimed to elucidate the role of SESN2 in the pathological process of osteoarthritis (OA), with a particular focus on its potential mechanism in regulating chondrocyte mitochondrial function. In vitro and in vivo inflammatory models were established using SpragueDawley rats via IL-1β stimulation and surgical destabilization of the medial meniscus (DMM). siRNA, overexpression plasmids, and adeno-associated viruses were used to investigate the role of SESN2 in OA progression, and mechanistic studies were performed to clarify the underlying pathways and downstream targets. SESN2 expression was significantly upregulated in the chondrocytes and cartilage tissues of OA rats. SESN2 overexpression exacerbated IL-1β-induced chondrocyte inflammation and DMM-induced cartilage damage (OARSI score, 2.000 [95% CI: 0.000-5.000]); conversely, SESN2 knockdown alleviated metabolic disorders and mitochondrial dysfunction in the matrix (Relative ATP content, 0.2639 [95% CI: 0.1068-0.4209]) and ameliorated cartilage degeneration in vivo (OARSI score, -2.000 [95% CI: -5.000 to -1.000]). Mechanistic studies revealed that SESN2 induced mitochondrial hyperfusion in chondrocytes (Mean branch length, 0.4821 [95% CI: 0.2707-0.6935]) and exacerbated mitochondrial dysfunction and inflammation via excessive mitochondrial fusion mediated by MFN2. Further investigation revealed that SESN2 upregulated MFN2 protein expression by promoting its dephosphorylation (Relative protein expression, 0.7693 [95% CI: 0.5392-0.9994]), thereby inducing mitochondrial hyperfusion. SESN2 promotes chondrocyte mitochondrial dysfunction and the pathological progression of OA by regulating MFN2 dephosphorylation to induce mitochondrial hyperfusion, thereby providing a new potential target for intervention in OA.

Objective: This study aims to explore the effects of exercise on gut microbiota and short-chain fatty acid (SCFA) metabolism, as well as its relationships with joint degeneration. Methods: To explore the impact of exercise on obesity-associated osteoarthritis (OA), rats were fed a high-fat/high-sucrose (HFS) diet with or without exercise. Histological staining and micro-computed tomography (micro-CT) were used to assess the effects of exercise on articular cartilage and subchondral bone. 16S rRNA sequencing and Gas Chromatography–Mass Spectrometry (GC-MS) were performed to analyze alteration in fecal gut microbiota and serum SCFAs. Results: Exercise prevented articular cartilage degeneration and subchondral bone loss in the HFS diet with exercise (HE) group compared to the HFS-diet control sedentary (HS) group. Gut microbiota analysis revealed that exercise reduced the relative abundances of families Lachnospiraceae, Ruminococcaceae, genera Ruminococcus, Colidextribacter, Caproiciproducens, and the unidentified genus of Lachnospiraceae, while increased the relative abundance of genus Akkermansia. Metabolomic analysis indicated exercise prevented AA reduction in the HE group. In addition, the level of AA was negatively correlated with OA severity and with the abundances of families Lachnospiraceae and Ruminococcaceae, genus Colidextribacter and the unidentified genus of Lachnospiraceae. Conclusions: Exercise effectively preserves the integrity of the cartilage–subchondral bone unit. The observed modifications in gut microbiota and AA levels following exercise intervention may be associated with the protective mechanisms against obesity-associated OA.