Mitochondrial dysfunction leads to osteoarthritis (OA) and disc degeneration. Hypoxia inducible factor-1α (HIF-1α) mediated mitophagy has a protective role in several diseases. However, the underlying mechanism of HIF-1α mediated mitophagy in OA remains largely unknown. This current study was performed to determine the effect of HIF-1α mediated mitophagy on OA. Therefore, X-ray and tissue staining including HE staining, safranin O-fast green (S-O) and Alcian Blue were used to assess imageology and histomorphology differences of mouse knee joint. Transcriptional analysis was used to find the possible targets in osteoarthritis. Western blot analysis, RT-qPCR and immunofluorescence staining were used to detect the changes in gene and protein levels in the vitro experiment. The expression of HIF-1α was increased in human and mouse OA cartilage. HIF-1α knockdown by siRNA further impair the hypoxia-induced mitochondrial dysfunction; In contrast, HIF-1α mediated protective role was reinforced by prolylhydroxylase (PHD) inhibitor dimethyloxalylglycine (DMOG). In addition, HIF-1α stabilization could alleviate apoptosis and senescence via mitophagy in chondrocytes under hypoxia condition, which could also ameliorate surgery-induced cartilage degradation in mice OA model. In conclusion, HIF-1α mediated mitophagy could alleviate OA, which may serve as a promising strategy for OA treatment.

Therapeutics used to treat central nervous system (CNS) injury were designed to repair neurites and inhibit cell apoptosis. Previous studies have shown that neuron-derived FGF10 exerts potential neuroprotective effects after cerebral ischemia injury. However, little is known about the role of endogenous FGF10 in the recovery process after spinal cord injury (SCI). In this study, we found that FGF10 is mainly produced by neuron and microglia/macrophages, and its expression is increased after SCI. Exogenous treatment of FGF10 improved functional recovery after injury by reducing apoptosis, as well as repairing neurites via FGFR2/PI3K/Akt pathway. On another hand, inhibiting the PI3K/Akt pathway with LY294002 partially reversed the therapeutic effects of FGF10. In addition, small interfering RNA knockdown of FGFR2 suppressed PI3K/Akt pathway activation by FGF10 and abolished its anti-apoptotic and neurite repair effects in vitro. Furthermore, FGF10 treatment inhibited the activation and proliferation of microglia/macrophages through regulation of TLR4/NF-κB pathway, and attenuated the release of pro-inflammatory cytokines after SCI. Thus, the increased expression of FGF10 after acute SCI is an endogenous self-protective response, suggesting that FGF10 could be a potential treatment for CNS injury.

Treatments for osteoarthritis (OA) are designed to restore chondrocyte function and inhibit cell apoptosis. Previous studies have shown that activation of the glucagon-like peptide-1 receptor (GLP-1R) leads to anti-inflammatory and anti-apoptotic effects. However, the role of GLP-1R in the pathological process of OA is unclear. In present work, we aimed to demonstrate the potential effect of GLP-1R on chondrocytes and elucidate its underlying mechanisms. We found that activation of GLP-1R with liraglutide could protect chondrocytes against endoplasmic reticulum stress and apoptosis induced by interleukin (IL)-1β or triglycerides (TGs). These effects were partially attenuated by GLP-1R small interfering RNA treatment. Moreover, inhibiting PI3K/Akt signaling abolished the protective effects of GLP-1R by increase the apoptosis activity and ER stress. Activating GLP-1R suppressed the nuclear factor kappa-B pathway, decreased the release of inflammatory mediators (IL-6, tumor necrosis factor α), and reduced matrix catabolism in TG-treated chondrocytes; these effects were abolished by GLP-1R knockdown. In the end, liraglutide attenuated rat cartilage degeneration in an OA model of knee joints in vivo. Our results indicate that GLP-1R is a therapeutic target for the treatment of OA, and that liraglutide could be a therapeutic candidate for this clinical application.

Intervertebral disc degeneration (IDD) is a complicated pathological condition blamed for low back pain. Mitochondrion is of vital importance for cellular homeostasis, and mitochondrial dysfunction is considered to be one of the major causes of cellular damage. Mitophagy is a cellular process to eliminate impaired mitochondria and showed protective effects in various diseases; however, its role in IDD is still not clear. Here, we explore the role of Parkin-mediated mitophagy in IDD. In this study, we found that Parkin was upregulated in degenerative nucleus pulposus (NP) tissues in vivo as well as in TNF-α stimulated NP cells in vitro. Knockdown of Parkin by siRNA showed that Parkin is crucial for apoptosis and mitochondrion homeostasis in NP cells. Further study showed that upregulation of Parkin by salidroside may eliminate impaired mitochondria and promote the survival of NP cells through activation of mitophagy in vitro. In in vivo study, we found that salidroside could inhibit the apoptosis of NP cells and ameliorate the progression of IDD. These results suggested that Parkin is involved in the pathogenesis of IDD and may be a potential therapeutic target for IDD.