Evidence suggests that intervertebral disc degeneration (IVDD) can be induced by Propionibacterium acnes (P. acnes), although the underlying mechanisms are unclear. In this study, we analyzed the pathological changes in degenerated human intervertebral discs (IVDs) infected with P. acnes. Compared with P. acnes-negative samples, P. acnes-positive IVDs showed increased apoptosis of nucleus pulposus cells (NPCs) concomitant with severe IVDD. Then, a P. acnes-inoculated IVD animal model was established, and severe IVDD was induced by P. acnes infection by promoting NPC apoptosis. The results suggested that P.acnes-induced apoptosis of NPCs via the Toll-like receptor 2 (TLR2)/c-Jun N-terminal kinase (JNK) pathway and mitochondrial-mediated cell death. In addition, P. acnes was found to activate autophagy, which likely plays a role in apoptosis of NPCs. Overall, these findings further validated the involvement of P. acnes in the pathology of IVDD and provided evidence that P. acnes-induced apoptosis of NPCs via the TLR2/JNK pathway is likely responsible for the pathology of IVDD.

P. acnes is significantly more likely to be present in herniated discs with an annular tear than in herniated discs without such a tear. Since in the vast majority of these cases, no P. acnes was found in control muscle samples, a true infection with P. acnes is far more likely than a contamination.

Purpose. To investigate whether P. acnes could induce disc degeneration and Modic changes when inoculated into the discs of rabbits. Method. A wild-type strain of P. acnes isolated from a patient associated with Modic change and disc degeneration was inoculated into the intervertebral discs of rabbits. Meanwhile, S. aureus was injected into the discs to establish a model of discitis as the comparison and a standard strain of P. acnes was inoculated as the control. MRI and histological change were observed. Results. Both the P. acnes-inoculated and S. aureus-inoculated rabbits showed hyperintense signals at endplates and hypointense signals at nucleus pulposus on T2WI. However, P. acnes only resulted in moderate disc degeneration and endplates rupture in histological examination, which was different from the pathological change of discitis caused by S. aureus. In addition, higher death rates (2/3 versus 0/5) were observed in S. aureus-inoculated rabbits. Conclusion. Compared to S. aureus, the pathological change caused by P. acnes would be considered as Modic-I change and disc degeneration rather than a discitis.

Four-octyl itaconate (4-OI) is the cell-permeable derivative of itaconate that can activate Nrf2 signaling by alkylating Keap1’s cysteine residues. Here, we tested the potential effect of 4-OI on hydrogen peroxide (H2O2)-induced oxidative injury in osteoblasts. In OB-6 cells and primary murine osteoblasts, 4-OI was able to activate Nrf2 signaling cascade and cause Keap1–Nrf2 disassociation, Nrf2 protein stabilization, cytosol accumulation, and nuclear translocation. 4-OI also augmented antioxidant-response element reporter activity and promoted expression of Nrf2-dependent genes (HO1, NQO1, and GCLC). Pretreatment with 4-OI inhibited H2O2-induced reactive oxygen species production, cell death, and apoptosis in osteoblasts. Furthermore, 4-OI inhibited H2O2-induced programmed necrosis by suppressing mitochondrial depolarization, mitochondrial cyclophilin D-ANT1 (adenine nucleotide translocase 1)-p53 association, and cytosol lactate dehydrogenase release in osteoblasts. Ectopic overexpression of immunoresponsive gene 1 (IRG1) increased endogenous itaconate production and activated Nrf2 signaling cascade, thereby inhibiting H2O2-induced oxidative injury and cell death. In OB-6 cells, Nrf2 silencing or CRISPR/Cas9-induced Nrf2 knockout blocked 4-OI-induced osteoblast cytoprotection against H2O2. Conversely, forced Nrf2 activation, by CRISPR/Cas9-induced Keap1 knockout, mimicked 4-OI-induced actions in OB-6 cells. Importantly, 4-OI was ineffective against H2O2 in Keap1-knockout cells. Collectively, 4-OI efficiently activates Nrf2 signaling to inhibit H2O2-induced oxidative injury and death of osteoblasts.

Normal oxygen level is critical for niches that together with other components of the niche play vital role in regulating stem or tumor cells behavior. Hypoxia plays an important role in normal development and disease progression, including the growth of solid tumors. The hypoxia inducible factors (HIFs) are the key mediators of the cellular response to hypoxia. In this review, we focused on the role of HIFs on bone tumor formation. Further, we also emphasized how hypoxia, stem cells, and its niches regulate the bone tumorigenesis.

An ultra-large structure-based virtual screening has discovered iKeap1 as a direct Keap1 inhibitor that can efficiently activate Nrf2 signaling. We here tested its potential effect against hydrogen peroxide (H2O2)-induced oxidative injury in osteoblasts. In primary murine and human osteoblasts, iKeap1 robustly activated Nrf2 signaling at micromole concentrations. iKeap1 disrupted Keap1-Nrf2 association, causing Nrf2 protein stabilization, cytosol accumulation and nuclear translocation in murine and human osteoblasts. The anti-oxidant response elements (ARE) activity and transcription of Nrf2-ARE-dependent genes (including HO1, NQO1 and GCLC) were increased as well. Significantly, iKeap1 pretreatment largely ameliorated H2O2-induced reactive oxygen species production, lipid peroxidation and DNA damage as well as cell apoptosis and programmed necrosis in osteoblasts. Moreover, dexamethasone- and nicotine-induced oxidative injury and apoptosis were alleviated by iKeap1. Importantly, Nrf2 shRNA or CRISPR/Cas9-induced Nrf2 knockout completely abolished iKeap1-induced osteoblast cytoprotection against H2O2. Conversely, CRISPR/Cas9-induced Keap1 knockout induced Nrf2 cascade activation and mimicked iKeap1-induced cytoprotective actions in murine osteoblasts. iKeap1 was ineffective against H2O2 in the Keap1-knockout murine osteoblasts. Collectively, iKeap1 activated Nrf2 signaling cascade to inhibit H2O2-induced oxidative injury and death of osteoblasts.

Latent P. acnes infection was associated with chronic inflammation in degenerated intervertebral discs, especially in the samples with visible bacteria in histology, which manifested as increased numbers of cytokines and neutrophils. Discs with P. acnes infection had much severer disc degeneration and P. acnes-associated chronic inflammation may be the reason.

Propionibacterium acnes (P. acnes), an important opportunistic anaerobic Gram-positive bacterium, causes bone and joint infections, discitis and spondylodiscitis. Accumulated evidence suggested that this microbe can colonise inside intervertebral discs without causing symptoms of discitis. Epidemiological investigation shows that the prevalence ranges from 13 % to 44 %. Furthermore, colonisation by P. acnes inside nonpyogenic intervertebral discs is thought to be one pathogen causing sciatica, Modic changes and nonspecific low back pain. Specially, patients can attain significant relief of low back pain, amelioration of Modic changes and alleviation of sciatica after antibiotic therapy, indicating the role of P. acnes in these pathological changes. However, until now, there were hypotheses only to explain problems such as how P. acnes access intervertebral discs and what the exact pathological mechanism it employs during its latent infection period. In addition, research regarding diagnostic procedures and treatment strategies were also rare. Overall, the prevalence and possible pathological role that P. acnes plays inside nonpyogenic intervertebral discs is summarised in this paper.